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Ye Q, Opoku G, Orlov M, Jaramillo AM, Holguin F, Vladar EK, Janssen WJ, Evans CM. Mucins and Their Roles in Asthma. Immunol Rev 2025; 331:e70034. [PMID: 40305069 DOI: 10.1111/imr.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Accepted: 04/21/2025] [Indexed: 05/02/2025]
Abstract
Mucus is a crucial component of airway host defense. For optimal protection, its chief components-the mucins MUC5AC and MUC5B-need to be tightly regulated. Their expression localizes to specific secretory epithelial cell types capable of producing and secreting massive glycopolymers. In asthma, abnormal mucus is an important clinical problem that is effectively treated with therapies that directly target mucins. This review summarizes what is known about how mucin gene regulation, protein synthesis, and secretion are regulated in healthy and asthmatic lungs. Ultimately, a better understanding of these processes could help identify novel ways of preventing or reversing airway mucus dysfunction.
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Affiliation(s)
- Qihua Ye
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
- Immunology PhD Program, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Gilda Opoku
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
- Integrated Physiology PhD Program, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Marika Orlov
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Ana M Jaramillo
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Fernando Holguin
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Eszter K Vladar
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
| | - William J Janssen
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
- Immunology PhD Program, University of Colorado School of Medicine, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, USA
| | - Christopher M Evans
- Division of Pulmonary Science and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
- Immunology PhD Program, University of Colorado School of Medicine, Denver, Colorado, USA
- Integrated Physiology PhD Program, University of Colorado School of Medicine, Denver, Colorado, USA
- Research Service, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, USA
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Lamm V, Huang K, Deng R, Cao S, Wang M, Soleymanjahi S, Promlek T, Rodgers R, Davis D, Nix D, Escudero GO, Xie Y, Chen CH, Gremida A, Rood RP, Liu TC, Baldridge MT, Deepak P, Davidson NO, Kaufman RJ, Ciorba MA. Tauroursodeoxycholic Acid (TUDCA) Reduces ER Stress and Lessens Disease Activity in Ulcerative Colitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.02.25322684. [PMID: 40236400 PMCID: PMC11998832 DOI: 10.1101/2025.04.02.25322684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Background and Aims In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC). Methods Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes. Results Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001). Conclusions Six weeks of oral TUDCA treatment was well-tolerated in patients with active ulcerative colitis and promoted mucosal healing, lessened ER stress, and reduced clinical disease activity. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted. Trial registration ClinicalTrials.gov (NCT04114292).
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Affiliation(s)
- Vladimir Lamm
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Katherine Huang
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Ruishu Deng
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Siyan Cao
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Miao Wang
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Saeed Soleymanjahi
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Thanyarat Promlek
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Rachel Rodgers
- Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Deanna Davis
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Darren Nix
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Guadalupe Oliva Escudero
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Yan Xie
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Chien-Huan Chen
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Anas Gremida
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Richard P Rood
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Megan T Baldridge
- Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Parakkal Deepak
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Nicholas O Davidson
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Randal J Kaufman
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Matthew A Ciorba
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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Takada S, Gallo S, Silva S, Tanaka H, Pincheira O, Zúñiga J, Villarroel M, Hidalgo X, Melo-Tanner J, Suzuki H, Machida S, Takahashi H, Miyake N. A Novel AGR2 Variant Causing Aberrant Monomer-Dimer Equilibrium Leading to Severe Respiratory and Digestive Symptoms. J Clin Immunol 2024; 45:55. [PMID: 39673647 PMCID: PMC11646215 DOI: 10.1007/s10875-024-01847-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 12/08/2024] [Indexed: 12/16/2024]
Abstract
Anterior gradient 2 (AGR2) is a protein disulfide isomerase that is important for protein processing in the endoplasmic reticulum and is essential for mucin production in the digestive and respiratory tracts. Bi-allelic AGR2 variants were recently found to cause recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD; MIM # 620233), although the mechanisms behind this condition remain unclear. To date, at least 15 patients with homozygous AGR2 variants have been reported. Here, we report two affected siblings in a consanguineous family who had recurrent respiratory infections and digestive symptoms, one of whom needed lung transplantation. To identify the genetic cause of their symptoms, we performed exome sequencing and identified a novel homozygous missense variant in AGR2 (NM_006408.4, c.250A>C, p.(Ser84Arg)) in both affected siblings. Both parents had the identical variant in a heterozygous state. This variant is quite rare in the general population and is clinically compatible with RIFTD, substituting a highly conserved CXXS motif with CXXR. We performed structural modeling and functional studies to investigate the effect of this variant. Through transient overexpression, Ser84Arg AGR2 decreased protein stability, and promoted aberrant dimerization under non-reducing conditions. AGR2 functions in a monomer-dimer equilibrium. Size-exclusion chromatography showed that the Ser84Arg mutant had a larger molecular size than the wild-type protein under non-reducing, but not reducing conditions, indicating that Ser84Arg enhanced intermolecular disulfide bonds. In conclusion, we identified a novel pathogenic AGR2 variant and indicated its abnormal monomer-dimer equilibrium as a possible mechanism involved in the pathogenesis of RIFTD.
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Affiliation(s)
- Sanami Takada
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Silvanna Gallo
- Department of Pediatrics, Immunology and Rheumatology Section, Hospital de Puerto Montt, Puerto Montt, Chile
- Escuela de Medicina, Universidad San Sebastián, Sede Patagonia, Puerto Montt, Chile
| | - Sebastian Silva
- Escuela de Medicina, Universidad San Sebastián, Sede Patagonia, Puerto Montt, Chile
- Child Neurology Service, Hospital de Puerto Montt, Puerto Montt, Chile
| | - Hiroki Tanaka
- Department of Structural Virology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Oscar Pincheira
- Pathological Anatomy Service, Hospital de Puerto Montt, Puerto Montt, Chile
| | - Juan Zúñiga
- Escuela de Medicina, Universidad San Sebastián, Sede Patagonia, Puerto Montt, Chile
- Department of Pediatrics, Respiratory Diseases Section, Hospital de Puerto Montt, Puerto Montt, Chile
| | - Marcela Villarroel
- Department of Pediatrics, Respiratory Diseases Section, Hospital de Puerto Montt, Puerto Montt, Chile
| | - Ximena Hidalgo
- Department of Pediatrics, Gastroenterology Section, Hospital de Puerto Montt, Puerto Montt, Chile
| | - Joel Melo-Tanner
- Instituto Nacional del Tórax, Santiago, Chile
- Clínica Las Condes, Santiago, Chile
| | - Hidefumi Suzuki
- Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Yokohama, Kanagawa, Japan
| | - Shinichi Machida
- Department of Structural Virology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hidehisa Takahashi
- Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Yokohama, Kanagawa, Japan
| | - Noriko Miyake
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
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Yue N, Hu P, Tian C, Kong C, Zhao H, Zhang Y, Yao J, Wei Y, Li D, Wang L. Dissecting Innate and Adaptive Immunity in Inflammatory Bowel Disease: Immune Compartmentalization, Microbiota Crosstalk, and Emerging Therapies. J Inflamm Res 2024; 17:9987-10014. [PMID: 39634289 PMCID: PMC11615095 DOI: 10.2147/jir.s492079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
The intestinal immune system is the largest immune organ in the human body. Excessive immune response to intestinal cavity induced by harmful stimuli including pathogens, foreign substances and food antigens is an important cause of inflammatory diseases such as celiac disease and inflammatory bowel disease (IBD). Although great progress has been made in the treatment of IBD by some immune-related biotherapeutic products, yet a considerable proportion of IBD patients remain unresponsive or immune tolerant to immunotherapeutic strategy. Therefore, it is necessary to further understand the mechanism of immune cell populations involved in enteritis, including dendritic cells, macrophages and natural lymphocytes, in the steady-state immune tolerance of IBD, in order to find effective IBD therapy. In this review, we discussed the important role of innate and adaptive immunity in the development of IBD. And the relationship between intestinal immune system disorders and microflora crosstalk were also presented. We also focus on the new findings in the field of T cell immunity, which might identify novel cytokines, chemokines or anti-cytokine antibodies as new approaches for the treatment of IBD.
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Affiliation(s)
- Ningning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Peng Hu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China
| | - Chengmei Tian
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Chen Kong
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Hailan Zhao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuqi Wei
- Department of Rehabilitation, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Defeng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
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Schraps N, Port JC, Menz A, Viehweger F, Büyücek S, Dum D, Schlichter R, Hinsch A, Fraune C, Bernreuther C, Kluth M, Hube‐Magg C, Möller K, Reiswich V, Luebke AM, Lebok P, Weidemann S, Sauter G, Lennartz M, Jacobsen F, Clauditz TS, Marx AH, Simon R, Steurer S, Mercanoglu B, Melling N, Hackert T, Burandt E, Gorbokon N, Minner S, Krech T, Lutz F. Prevalence and Significance of AGR2 Expression in Human Cancer. Cancer Med 2024; 13:e70407. [PMID: 39533806 PMCID: PMC11557986 DOI: 10.1002/cam4.70407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
BACKROUND Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing. METHODS To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). RESULTS AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%-100%), urothelial carcinoma (74.6%-100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%-99.6%), and pancreaticobiliary cancers (65.2%-98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%-77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades as well as advanced pT stage (p = 0.0035) in clear cell renal cell carcinoma (ccRCC). Low AGR2 expression was associated with high BRE grade in breast cancer (p = 0.0049), nodal metastasis (p = 0.0275) and RAS mutation (p = 0.0136) in colorectal cancer, nodal metastasis (p = 0.0482) in endometrioid endometrial carcinoma, high grade in noninvasive urothelial carcinoma (p = 0.0003), and invasive tumor growth in urothelial carcinoma (p < 0.0001). CONCLUSIONS It is concluded that AGR2 expression occurs in a broad range of different tumor entities and that AGR2 assessment may serve as a diagnostic aid for the distinction of thyroidal neoplasms and as a prognostic marker in various cancer types.
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Affiliation(s)
- Nina Schraps
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | | | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Seyma Büyücek
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Ria Schlichter
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
- Institute of Pathology, Clinical Center OsnabrueckOsnabrueckGermany
| | | | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Claudia Hube‐Magg
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Viktor Reiswich
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Andreas M. Luebke
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
- Institute of Pathology, Clinical Center OsnabrueckOsnabrueckGermany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Till S. Clauditz
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Andreas H. Marx
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
- Department of PathologyAcademic Hospital FuerthFuerthGermany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Stefan Steurer
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Baris Mercanoglu
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Nathaniel Melling
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Thilo Hackert
- Institute of Pathology, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Eike Burandt
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Natalia Gorbokon
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Sarah Minner
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Till Krech
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- Institute of Pathology, Clinical Center OsnabrueckOsnabrueckGermany
| | - Florian Lutz
- General, Visceral and Thoracic Surgery Department and ClinicUniversity Medical Center Hamburg‐EppendorfHamburgGermany
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Liu Y, Xu C, Gu R, Han R, Li Z, Xu X. Endoplasmic reticulum stress in diseases. MedComm (Beijing) 2024; 5:e701. [PMID: 39188936 PMCID: PMC11345536 DOI: 10.1002/mco2.701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/28/2024] Open
Abstract
The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.
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Affiliation(s)
- Yingying Liu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
| | - Chunling Xu
- School of Pharmaceutical SciencesTsinghua UniversityBeijingChina
| | - Renjun Gu
- School of Chinese MedicineNanjing University of Chinese MedicineNanjingChina
- Department of Gastroenterology and HepatologyJinling HospitalMedical School of Nanjing UniversityNanjingChina
| | - Ruiqin Han
- State Key Laboratory of Medical Molecular BiologyDepartment of Biochemistry and Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ziyu Li
- School of Acupuncture and TuinaSchool of Regimen and RehabilitationNanjing University of Chinese MedicineNanjingChina
| | - Xianrong Xu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
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7
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Timmermans S, Wallaeys C, Garcia-Gonzalez N, Pollaris L, Saeys Y, Libert C. Identification and Characterization of Multiple Paneth Cell Types in the Mouse Small Intestine. Cells 2024; 13:1435. [PMID: 39273007 PMCID: PMC11394207 DOI: 10.3390/cells13171435] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/09/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
The small intestinal crypts harbor secretory Paneth cells (PCs) which express bactericidal peptides that are crucial for maintaining intestinal homeostasis. Considering the diverse environmental conditions throughout the course of the small intestine, multiple subtypes of PCs are expected to exist. We applied single-cell RNA-sequencing of PCs combined with deep bulk RNA-sequencing on PC populations of different small intestinal locations and discovered several expression-based PC clusters. Some of these are discrete and resemble tuft cell-like PCs, goblet cell (GC)-like PCs, PCs expressing stem cell markers, and atypical PCs. Other clusters are less discrete but appear to be derived from different locations along the intestinal tract and have environment-dictated functions such as food digestion and antimicrobial peptide production. A comprehensive spatial analysis using Resolve Bioscience was conducted, leading to the identification of different PC's transcriptomic identities along the different compartments of the intestine, but not between PCs in the crypts themselves.
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Affiliation(s)
- Steven Timmermans
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (S.T.); (C.W.); (N.G.-G.); (L.P.); (Y.S.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Charlotte Wallaeys
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (S.T.); (C.W.); (N.G.-G.); (L.P.); (Y.S.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Natalia Garcia-Gonzalez
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (S.T.); (C.W.); (N.G.-G.); (L.P.); (Y.S.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Lotte Pollaris
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (S.T.); (C.W.); (N.G.-G.); (L.P.); (Y.S.)
- Department of Applied Mathematics, Computer Science and Statistics, Ghent University, 9000 Ghent, Belgium
| | - Yvan Saeys
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (S.T.); (C.W.); (N.G.-G.); (L.P.); (Y.S.)
- Department of Applied Mathematics, Computer Science and Statistics, Ghent University, 9000 Ghent, Belgium
| | - Claude Libert
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (S.T.); (C.W.); (N.G.-G.); (L.P.); (Y.S.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
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8
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Jaramillo AM, Vladar EK, Holguin F, Dickey BF, Evans CM. Emerging cell and molecular targets for treating mucus hypersecretion in asthma. Allergol Int 2024; 73:375-381. [PMID: 38692992 PMCID: PMC11491148 DOI: 10.1016/j.alit.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/03/2024] Open
Abstract
Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in the biology of mucin glycoproteins with a specific focus on MUC5AC and MUC5B, the chief macromolecular components of airway mucus. An improved mechanistic understanding of key steps in mucin production and secretion will help reveal novel potential therapeutic strategies.
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Affiliation(s)
- Ana M Jaramillo
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Eszter K Vladar
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Fernando Holguin
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Burton F Dickey
- Department of Pulmonary Medicine, Anderson Cancer Center, University of Texas M.D., Houston, TX, USA
| | - Christopher M Evans
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
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9
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Vivacqua G, Mancinelli R, Leone S, Vaccaro R, Garro L, Carotti S, Ceci L, Onori P, Pannarale L, Franchitto A, Gaudio E, Casini A. Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders. Neurogastroenterol Motil 2024; 36:e14780. [PMID: 38462652 DOI: 10.1111/nmo.14780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 01/27/2024] [Accepted: 03/03/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND Different studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis. PURPOSE In this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut-to-brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders.
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Affiliation(s)
- Giorgio Vivacqua
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Stefano Leone
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Rosa Vaccaro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Ludovica Garro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Simone Carotti
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Rome, Italy
| | - Ludovica Ceci
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Arianna Casini
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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10
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Becker B, Wottawa F, Bakr M, Koncina E, Mayr L, Kugler J, Yang G, Windross SJ, Neises L, Mishra N, Harris D, Tran F, Welz L, Schwärzler J, Bánki Z, Stengel ST, Ito G, Krötz C, Coleman OI, Jaeger C, Haller D, Paludan SR, Blumberg R, Kaser A, Cicin-Sain L, Schreiber S, Adolph TE, Letellier E, Rosenstiel P, Meiser J, Aden K. Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut. iScience 2024; 27:109173. [PMID: 38496294 PMCID: PMC10943449 DOI: 10.1016/j.isci.2024.109173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/27/2023] [Accepted: 02/06/2024] [Indexed: 03/19/2024] Open
Abstract
Inflammatory bowel diseases are characterized by the chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER stress on the pathophysiology of IBD remain unclear. By using in vitro, in vivo models, and patient datasets, we identified a distinct polarization of the mitochondrial one-carbon metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon ER stress. This metabolic phenotype strongly correlates with IBD severity and therapy response. Mechanistically, we uncover that both chronic ER stress and serine limitation disrupt cGAS-STING signaling, impairing the epithelial response against viral and bacterial infection and fueling experimental enteritis. Consequently, the antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of serine metabolism to allow proper cGAS-STING signaling and innate immune responses upon gut inflammation.
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Affiliation(s)
- Björn Becker
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
| | - Felix Wottawa
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Mohamed Bakr
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Eric Koncina
- Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Université du Luxembourg, Luxembourg, Luxembourg
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Julia Kugler
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Guang Yang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | | | - Laura Neises
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
| | - Neha Mishra
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Danielle Harris
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Lina Welz
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Zoltán Bánki
- Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Innsbruck, Austria
| | - Stephanie T. Stengel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Go Ito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Christina Krötz
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
| | - Olivia I. Coleman
- Chair of Nutrition and Immunology, TUM School of Life Sciences, Technical University of Munich, Luxembourg, Luxembourg
| | - Christian Jaeger
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Dirk Haller
- Chair of Nutrition and Immunology, TUM School of Life Sciences, Technical University of Munich, Luxembourg, Luxembourg
- ZIEL-Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany
| | | | - Richard Blumberg
- Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, England, UK
| | - Luka Cicin-Sain
- Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Elisabeth Letellier
- Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Université du Luxembourg, Luxembourg, Luxembourg
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Johannes Meiser
- Luxembourg Institute of Health, Department of Cancer Research, Luxembourg, Luxembourg
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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11
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Neidhardt L, Cloots E, Friemel N, Weiss CAM, Harding HP, McLaughlin SH, Janssens S, Ron D. The IRE1β-mediated unfolded protein response is repressed by the chaperone AGR2 in mucin producing cells. EMBO J 2024; 43:719-753. [PMID: 38177498 PMCID: PMC10907699 DOI: 10.1038/s44318-023-00014-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 11/07/2023] [Accepted: 11/15/2023] [Indexed: 01/06/2024] Open
Abstract
Effector mechanisms of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) are well-characterised, but how ER proteostasis is sensed is less well understood. Here, we exploited the beta isoform of the UPR transducer IRE1, that is specific to mucin-producing cells in order to gauge the relative regulatory roles of activating ligands and repressing chaperones of the specialised ER of goblet cells. Replacement of the stress-sensing luminal domain of endogenous IRE1α in CHO cells (normally expressing neither mucin nor IRE1β) with the luminal domain of IRE1β deregulated basal IRE1 activity. The mucin-specific chaperone AGR2 repressed IRE1 activity in cells expressing the domain-swapped IRE1β/α chimera, but had no effect on IRE1α. Introduction of the goblet cell-specific client MUC2 reversed AGR2-mediated repression of the IRE1β/α chimera. In vitro, AGR2 actively de-stabilised the IRE1β luminal domain dimer and formed a reversible complex with the inactive monomer. These features of the IRE1β-AGR2 couple suggest that active repression of IRE1β by a specialised mucin chaperone subordinates IRE1 activity to a proteostatic challenge unique to goblet cells, a challenge that is otherwise poorly recognised by the pervasive UPR transducers.
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Affiliation(s)
- Lisa Neidhardt
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
| | - Eva Cloots
- Laboratory for ER stress and Inflammation, VIB Center for Inflammation Research, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
- Department of Pediatrics and Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Natalie Friemel
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Caroline A M Weiss
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Heather P Harding
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Stephen H McLaughlin
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
| | - Sophie Janssens
- Laboratory for ER stress and Inflammation, VIB Center for Inflammation Research, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
- Department of Pediatrics and Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - David Ron
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
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12
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Zhang F, Chen M, Liu X, Ji X, Li S, Jin E. New insights into the unfolded protein response (UPR)-anterior gradient 2 (AGR2) pathway in the regulation of intestinal barrier function in weaned piglets. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2023; 15:225-232. [PMID: 38033605 PMCID: PMC10685161 DOI: 10.1016/j.aninu.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 07/05/2023] [Accepted: 08/11/2023] [Indexed: 12/02/2023]
Abstract
Sustained dysfunction of the intestinal barrier caused by early weaning is a major factor that induces postweaning diarrhea in weaned piglets. In both healthy and diseased states, the intestinal barrier is regulated by goblet cells. Alterations in the characteristics of goblet cells are linked to intestinal barrier dysfunction and inflammatory conditions during pathogenic infections. In this review, we summarize the current understanding of the mechanisms of the unfolded protein response (UPR) and anterior gradient 2 (AGR2) in maintaining intestinal barrier function and how modifications to these systems affect mucus barrier characteristics and goblet cell dysregulation. We highlight a novel mechanism underlying the UPR-AGR2 pathway, which affects goblet cell differentiation and maturation and the synthesis and secretion of mucin by regulating epidermal growth factor receptor and mucin 2. This study provides a theoretical basis and new insights into the regulation of intestinal health in weaned piglets.
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Affiliation(s)
- Feng Zhang
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
- Anhui Province Key Laboratory of Animal Nutrition Regulation and Health, Chuzhou, China
| | - Mengxian Chen
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
| | - Xiaodan Liu
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
| | - Xu Ji
- Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, Institute of Animal Science and Veterinary Medicine, Anhui Academy of Agricultural Sciences, Hefei, China
| | - Shenghe Li
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
- Anhui Province Key Laboratory of Animal Nutrition Regulation and Health, Chuzhou, China
| | - Erhui Jin
- College of Animal Science, Anhui Science and Technology University, Chuzhou, China
- Anhui Province Key Laboratory of Animal Nutrition Regulation and Health, Chuzhou, China
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13
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Liu W, Fan X, Jian B, Wen D, Wang H, Liu Z, Li B. The signaling pathway of hypoxia inducible factor in regulating gut homeostasis. Front Microbiol 2023; 14:1289102. [PMID: 37965556 PMCID: PMC10641782 DOI: 10.3389/fmicb.2023.1289102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 10/02/2023] [Indexed: 11/16/2023] Open
Abstract
Hypoxia represent a condition in which an adequate amount of oxygen supply is missing in the body, and it could be caused by a variety of diseases, including gastrointestinal disorders. This review is focused on the role of hypoxia in the maintenance of the gut homeostasis and related treatment of gastrointestinal disorders. The effects of hypoxia on the gut microbiome and its role on the intestinal barrier functionality are also covered, together with the potential role of hypoxia in the development of gastrointestinal disorders, including inflammatory bowel disease and irritable bowel syndrome. Finally, we discussed the potential of hypoxia-targeted interventions as a novel therapeutic approach for gastrointestinal disorders. In this review, we highlighted the importance of hypoxia in the maintenance of the gut homeostasis and the potential implications for the treatment of gastrointestinal disorders.
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Affiliation(s)
- Wei Liu
- Institute of Animal Husbandry and Veterinary, Tibet Academy of Agricultural and Animal Husbandry Sciences, Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lhasa, China
- School of Public Health, Lanzhou University, Lanzhou, China
| | - Xueni Fan
- Institute of Animal Husbandry and Veterinary, Tibet Academy of Agricultural and Animal Husbandry Sciences, Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lhasa, China
- School of Public Health, Lanzhou University, Lanzhou, China
| | - Boshuo Jian
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, China
| | - Dongxu Wen
- Institute of Animal Husbandry and Veterinary, Tibet Academy of Agricultural and Animal Husbandry Sciences, Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lhasa, China
| | - Hongzhuang Wang
- Institute of Animal Husbandry and Veterinary, Tibet Academy of Agricultural and Animal Husbandry Sciences, Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lhasa, China
| | - Zhenjiang Liu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, China
| | - Bin Li
- Institute of Animal Husbandry and Veterinary, Tibet Academy of Agricultural and Animal Husbandry Sciences, Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lhasa, China
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14
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Gutierrez A, Pucket B, Engevik MA. Bifidobacterium and the intestinal mucus layer. MICROBIOME RESEARCH REPORTS 2023; 2:36. [PMID: 38045921 PMCID: PMC10688832 DOI: 10.20517/mrr.2023.37] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/21/2023] [Accepted: 09/13/2023] [Indexed: 12/05/2023]
Abstract
Bifidobacterium species are integral members of the human gut microbiota and these microbes have significant interactions with the intestinal mucus layer. This review delves into Bifidobacterium-mucus dynamics, shedding light on the multifaceted nature of this relationship. We cover conserved features of Bifidobacterium-mucus interactions, such as mucus adhesion and positive regulation of goblet cell and mucus production, as well as species and strain-specific attributes of mucus degradation. For each interface, we explore the molecular mechanisms underlying these interactions and their potential implications for human health. Notably, we emphasize the ability of Bifidobacterium species to positively influence the mucus layer, shedding light on its potential as a mucin-builder and a therapeutic agent for diseases associated with disrupted mucus barriers. By elucidating the complex interplay between Bifidobacterium and intestinal mucus, we aim to contribute to a deeper understanding of the gut microbiota-host interface and pave the way for novel therapeutic strategies.
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Affiliation(s)
- Alyssa Gutierrez
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Brenton Pucket
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Melinda A. Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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15
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Kosykh AV, Tereshina MB, Gurskaya NG. Potential Role of AGR2 for Mammalian Skin Wound Healing. Int J Mol Sci 2023; 24:ijms24097895. [PMID: 37175601 PMCID: PMC10178616 DOI: 10.3390/ijms24097895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The limited ability of mammals to regenerate has garnered significant attention, particularly in regard to skin wound healing (WH), which is a critical step for regeneration. In human adults, skin WH results in the formation of scars following injury or trauma, regardless of severity. This differs significantly from the scarless WH observed in the fetal skin of mammals or anamniotes. This review investigates the role of molecular players involved in scarless WH, which are lost or repressed in adult mammalian WH systems. Specifically, we analyze the physiological role of Anterior Gradient (AGR) family proteins at different stages of the WH regulatory network. AGR is activated in the regeneration of lower vertebrates at the stage of wound closure and, accordingly, is important for WH. Mammalian AGR2 is expressed during scarless WH in embryonic skin, while in adults, the activity of this gene is normally inhibited and is observed only in the mucous epithelium of the digestive tract, which is capable of full regeneration. The combination of AGR2 unique potencies in postnatal mammals makes it possible to consider it as a promising candidate for enhancing WH processes.
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Affiliation(s)
- Anastasiya V Kosykh
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Maria B Tereshina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
| | - Nadya G Gurskaya
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
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16
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ERdj5 protects goblet cells from endoplasmic reticulum stress-mediated apoptosis under inflammatory conditions. Exp Mol Med 2023; 55:401-412. [PMID: 36759578 PMCID: PMC9981579 DOI: 10.1038/s12276-023-00945-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 11/21/2022] [Accepted: 12/06/2022] [Indexed: 02/11/2023] Open
Abstract
Endoplasmic reticulum stress is closely associated with the onset and progression of inflammatory bowel disease. ERdj5 is an endoplasmic reticulum-resident protein disulfide reductase that mediates the cleavage and degradation of misfolded proteins. Although ERdj5 expression is significantly higher in the colonic tissues of patients with inflammatory bowel disease than in healthy controls, its role in inflammatory bowel disease has not yet been reported. In the current study, we used ERdj5-knockout mice to investigate the potential roles of ERdj5 in inflammatory bowel disease. ERdj5 deficiency causes severe inflammation in mouse colitis models and weakens gut barrier function by increasing NF-κB-mediated inflammation. ERdj5 may not be indispensable for goblet cell function under steady-state conditions, but its deficiency induces goblet cell apoptosis under inflammatory conditions. Treatment of ERdj5-knockout mice with the chemical chaperone ursodeoxycholic acid ameliorated severe colitis by reducing endoplasmic reticulum stress. These findings highlight the important role of ERdj5 in preserving goblet cell viability and function by resolving endoplasmic reticulum stress.
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17
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Ilani T, Reznik N, Yeshaya N, Feldman T, Vilela P, Lansky Z, Javitt G, Shemesh M, Brenner O, Elkis Y, Varsano N, Jaramillo AM, Evans CM, Fass D. The disulfide catalyst QSOX1 maintains the colon mucosal barrier by regulating Golgi glycosyltransferases. EMBO J 2023; 42:e111869. [PMID: 36245281 PMCID: PMC9841341 DOI: 10.15252/embj.2022111869] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/25/2022] [Accepted: 09/29/2022] [Indexed: 01/27/2023] Open
Abstract
Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide-mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide-mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.
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Affiliation(s)
- Tal Ilani
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Nava Reznik
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Noa Yeshaya
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Tal Feldman
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Patrick Vilela
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Zipora Lansky
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Gabriel Javitt
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Michal Shemesh
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Ori Brenner
- Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel
| | | | - Neta Varsano
- Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel
| | - Ana M Jaramillo
- Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA
| | - Christopher M Evans
- Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA.,Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, USA
| | - Deborah Fass
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
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18
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Hussein D, Alsereihi R, Salwati AAA, Algehani R, Alhowity A, Al-Hejin AM, Schulten HJ, Baeesa S, Bangash M, Alghamdi F, Cross R, Al Zughaibi T, Saka M, Chaudhary A, Abuzenadah A. The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses. Cancer Cell Int 2022; 22:387. [PMID: 36482387 PMCID: PMC9730595 DOI: 10.1186/s12935-022-02814-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Glioblastomas (GBs) are characterised as one of the most aggressive primary central nervous system tumours (CNSTs). Single-cell sequencing analysis identified the presence of a highly heterogeneous population of cancer stem cells (CSCs). The proteins anterior gradient homologue 2 (AGR2) and glucose-regulated protein 78 (GRP78) are known to play critical roles in regulating unfolded protein response (UPR) machinery. The UPR machinery influences cell survival, migration, invasion and drug resistance. Hence, we investigated the role of AGR2 in drug-resistant recurrent glioblastoma cells. METHODS Immunofluorescence, biological assessments and whole exome sequencing analyses were completed under in situ and in vitro conditions. Cells were treated with CNSTs clinical/preclinical drugs taxol, cisplatin, irinotecan, MCK8866, etoposide, and temozolomide, then resistant cells were analysed for the expression of AGR2. AGR2 was repressed using single and double siRNA transfections and combined with either temozolomide or irinotecan. RESULTS Genomic and biological characterisations of the AGR2-expressed Jed66_GB and Jed41_GB recurrent glioblastoma tissues and cell lines showed features consistent with glioblastoma. Immunofluorescence data indicated that AGR2 co-localised with the UPR marker GRP78 in both the tissue and their corresponding primary cell lines. AGR2 and GRP78 were highly expressed in glioblastoma CSCs. Following treatment with the aforementioned drugs, all drug-surviving cells showed high expression of AGR2. Prolonged siRNA repression of a particular region in AGR2 exon 2 reduced AGR2 protein expression and led to lower cell densities in both cell lines. Co-treatments using AGR2 exon 2B siRNA in conjunction with temozolomide or irinotecan had partially synergistic effects. The slight reduction of AGR2 expression increased nuclear Caspase-3 activation in both cell lines and caused multinucleation in the Jed66_GB cell line. CONCLUSIONS AGR2 is highly expressed in UPR-active CSCs and drug-resistant GB cells, and its repression leads to apoptosis, via multiple pathways.
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Affiliation(s)
- Deema Hussein
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Reem Alsereihi
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Biological Sciences, Faculty of Science, King Abdulaziz University, 80203, Jeddah, 21589 Saudi Arabia ,College of Health Sciences, Al-Rayan Colleges, 41411, Madinah AL-Munawarah, Saudi Arabia
| | - Abdulla Ahmed A. Salwati
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia
| | - Rinad Algehani
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia
| | - Alazouf Alhowity
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia
| | - Ahmed M. Al-Hejin
- grid.412125.10000 0001 0619 1117Department of Biological Sciences, Faculty of Science, King Abdulaziz University, 80203, Jeddah, 21589 Saudi Arabia
| | - Hans-Juergen Schulten
- grid.412125.10000 0001 0619 1117Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Saleh Baeesa
- grid.412125.10000 0001 0619 1117Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Mohammed Bangash
- grid.412125.10000 0001 0619 1117Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Fahad Alghamdi
- grid.412125.10000 0001 0619 1117Pathology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Richard Cross
- grid.48815.300000 0001 2153 2936School of Engineering and Sustainable Development, Emerging Technologies Research Centre (EMTERC), De Montfort University, The Gateway, Leicester, LE1 9BH UK
| | - Torki Al Zughaibi
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Mohamad Saka
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Adeel Chaudhary
- grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Centre of Innovation for Personalized Medicine, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
| | - Adel Abuzenadah
- grid.412125.10000 0001 0619 1117King Fahd Medical Research Center, King Abdulaziz University, 80216, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia ,grid.412125.10000 0001 0619 1117Centre of Innovation for Personalized Medicine, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
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19
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Gustafsson JK, Johansson MEV. The role of goblet cells and mucus in intestinal homeostasis. Nat Rev Gastroenterol Hepatol 2022; 19:785-803. [PMID: 36097076 DOI: 10.1038/s41575-022-00675-x] [Citation(s) in RCA: 272] [Impact Index Per Article: 90.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/04/2022] [Indexed: 12/08/2022]
Abstract
The intestinal tract faces numerous challenges that require several layers of defence. The tight epithelium forms a physical barrier that is further protected by a mucus layer, which provides various site-specific protective functions. Mucus is produced by goblet cells, and as a result of single-cell RNA sequencing identifying novel goblet cell subpopulations, our understanding of their various contributions to intestinal homeostasis has improved. Goblet cells not only produce mucus but also are intimately linked to the immune system. Mucus and goblet cell development is tightly regulated during early life and synchronized with microbial colonization. Dysregulation of the developing mucus systems and goblet cells has been associated with infectious and inflammatory conditions and predisposition to chronic disease later in life. Dysfunctional mucus and altered goblet cell profiles are associated with inflammatory conditions in which some mucus system impairments precede inflammation, indicating a role in pathogenesis. In this Review, we present an overview of the current understanding of the role of goblet cells and the mucus layer in maintaining intestinal health during steady-state and how alterations to these systems contribute to inflammatory and infectious disease.
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Affiliation(s)
- Jenny K Gustafsson
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Malin E V Johansson
- Department of Medical Biochemisty and Cell biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
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20
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Viladomiu M, Khounlotham M, Dogan B, Lima SF, Elsaadi A, Cardakli E, Castellanos JG, Ng C, Herzog J, Schoenborn AA, Ellermann M, Liu B, Zhang S, Gulati AS, Sartor RB, Simpson KW, Lipkin SM, Longman RS. Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103 + dendritic cell IL-23-dependent ileocolitis. Cell Rep 2022; 41:111637. [PMID: 36384110 PMCID: PMC9805753 DOI: 10.1016/j.celrep.2022.111637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/06/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is associated with Crohn's disease (CD), but its impact on host-microbe interaction in disease pathogenesis is not well defined. Functional deficiency in the protein disulfide isomerase anterior gradient 2 (AGR2) has been linked with CD and leads to epithelial cell ER stress and ileocolitis in mice and humans. Here, we show that ileal expression of AGR2 correlates with mucosal Enterobactericeae abundance in human inflammatory bowel disease (IBD) and that Agr2 deletion leads to ER-stress-dependent expansion of mucosal-associated adherent-invasive Escherichia coli (AIEC), which drives Th17 cell ileocolitis in mice. Mechanistically, our data reveal that AIEC-induced epithelial cell ER stress triggers CD103+ dendritic cell production of interleukin-23 (IL-23) and that IL-23R is required for ileocolitis in Agr2-/- mice. Overall, these data reveal a specific and reciprocal interaction of the expansion of the CD pathobiont AIEC with ER-stress-associated ileocolitis and highlight a distinct cellular mechanism for IL-23-dependent ileocolitis.
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Affiliation(s)
- Monica Viladomiu
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Manirath Khounlotham
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Belgin Dogan
- College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Svetlana F. Lima
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ahmed Elsaadi
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Emre Cardakli
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jim G. Castellanos
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Charles Ng
- Department of Pathology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jeremy Herzog
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alexi A. Schoenborn
- Department of Pediatrics, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Melissa Ellermann
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA,Present address: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Bo Liu
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shiying Zhang
- College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Ajay S. Gulati
- Department of Pediatrics, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - R. Balfour Sartor
- Departments of Medicine and Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kenneth W. Simpson
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA,College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Steven M. Lipkin
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA,Correspondence: (S.M.L.), (R.S.L.)
| | - Randy S. Longman
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA,Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA,Lead contact,Correspondence: (S.M.L.), (R.S.L.)
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21
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Boisteau E, Posseme C, Di Modugno F, Edeline J, Coulouarn C, Hrstka R, Martisova A, Delom F, Treton X, Eriksson LA, Chevet E, Lièvre A, Ogier-Denis E. Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology. Oncogene 2022; 41:4673-4685. [PMID: 36068336 DOI: 10.1038/s41388-022-02452-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 08/03/2022] [Accepted: 08/23/2022] [Indexed: 11/09/2022]
Abstract
Most of the organs of the digestive tract comprise secretory epithelia that require specialized molecular machines to achieve their functions. As such anterior gradient (AGR) proteins, which comprise AGR1, AGR2, and AGR3, belong to the protein disulfide isomerase family, and are involved in secretory and transmembrane protein biogenesis in the endoplasmic reticulum. They are generally expressed in epithelial cells with high levels in most of the digestive tract epithelia. To date, the vast majority of the reports concern AGR2, which has been shown to exhibit various subcellular localizations and exert pro-oncogenic functions. AGR2 overexpression has recently been associated with a poor prognosis in digestive cancers. AGR2 is also involved in epithelial homeostasis. Its deletion in mice results in severe diffuse gut inflammation, whereas in inflammatory bowel diseases, the secretion of AGR2 in the extracellular milieu participates in the reshaping of the cellular microenvironment. AGR2 thus plays a key role in inflammation and oncogenesis and may represent a therapeutic target of interest. In this review, we summarize the already known roles and mechanisms of action of the AGR family proteins in digestive diseases, their expression in the healthy digestive tract, and in digestive oncology. At last, we discuss the potential diagnostic and therapeutic implications underlying the biology of AGR proteins.
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Affiliation(s)
- Emeric Boisteau
- INSERM U1242, University of Rennes, Rennes, France
- Department of Gastroenterology, University Hospital Pontchaillou, University of Rennes, Rennes, France
| | - Céline Posseme
- INSERM U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Federico Di Modugno
- INSERM U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Julien Edeline
- INSERM U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | | | - Roman Hrstka
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Andrea Martisova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
- National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic
| | | | - Xavier Treton
- Assistance Publique-Hôpitaux de Paris, University of Paris, Clichy, France
| | - Leif A Eriksson
- Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
| | - Eric Chevet
- INSERM U1242, University of Rennes, Rennes, France.
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
| | - Astrid Lièvre
- INSERM U1242, University of Rennes, Rennes, France.
- Department of Gastroenterology, University Hospital Pontchaillou, University of Rennes, Rennes, France.
| | - Eric Ogier-Denis
- INSERM U1242, University of Rennes, Rennes, France.
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
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22
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Trehalose Attenuates Oxidative Stress and Endoplasmic Reticulum Stress-Mediated Apoptosis in IPEC-J2 Cells Subjected to Heat Stress. Animals (Basel) 2022; 12:ani12162093. [PMID: 36009683 PMCID: PMC9405045 DOI: 10.3390/ani12162093] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 11/22/2022] Open
Abstract
This study was carried out to investigate the effects of trehalose (Tre) on antioxidant capacity, endoplasmic reticulum stress (ERS) response and apoptosis of heat-stressed intestinal porcine epithelial cells (IPEC-J2). IPEC-J2 cells were cultured at 37 °C until the end of the experiment (control, CON); exposed to heat stress for 2 h (43 °C, HS); or pretreated with 0.1, 1, 5, 10, and 15 mM trehalose at 37 °C for 4 h prior to heat stress exposure for 2 h. The optimum level of trehalose for protecting against HS-induced cell injuries was determined to be 10 mM, as evidenced by the highest cellular viability and lowest malondialdehyde (MDA) content and lactate dehydrogenase (LDH) activity. Based on these, IPEC-J2 cells were divided into three groups: the first group was cultured at 37 °C until the end of the experiment (control, CON); the second group was exposed to heat stress for 2 h (43 °C, HS); the third group was pretreated with 10 mM trehalose for 4 h at 37 °C prior to heat stress exposure for 2 h (Tre + HS). The reactive oxygen species (ROS) content, superoxide dismutase (SOD) activity, mitochondrial membrane potential (MMP) changes, and expressions of the manganese superoxide dismutase (SOD2), ERS and apoptosis-related proteins were determined. Compared to the CON group, HS significantly increased ROS generation (p < 0.01), decreased SOD activity (p < 0.05), and downregulated protein expression of SOD2 (p < 0.01). Compared to the HS group, Tre supplementation reduced ROS levels and increased SOD activity and SOD2 expression to the levels that were comparable to the control (p < 0.05). The HS-induced ERS response was evidenced by the increased protein expressions of glucose-regulated protein 78 (GRP78) (p < 0.01), eukaryotic translation initiation factor 2α (p-eif2α) (p < 0.01), transcription activator 4 (ATF4) (p < 0.01), and the protein expression of C/EBP homologous protein (CHOP) (p < 0.01), which were the four hallmarks of ERS. The Tre + HS group showed lower expressions of GRP78 (p < 0.01), p-eif2α (p < 0.01), ATF4 (p < 0.01), and CHOP (p < 0.01) than that of the HS group. Tre pretreatment attenuated HS-induced mitochondrial apoptosis in IPEC-J2 cells, demonstrated by the increased MMP and decreased proapoptotic proteins active caspase 3, Bax, and cytochrome c (Cyt c). Taken together, trehalose can protect against HS-induced oxidative damage and endoplasmic reticulum stress-mediated apoptosis in IPEC-J2 cells. These data may provide a nutritional strategy for alleviating heat stress in pig production.
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23
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Glover JS, Browning BD, Ticer TD, Engevik AC, Engevik MA. Acinetobacter calcoaceticus is Well Adapted to Withstand Intestinal Stressors and Modulate the Gut Epithelium. Front Physiol 2022; 13:880024. [PMID: 35685287 PMCID: PMC9170955 DOI: 10.3389/fphys.2022.880024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 04/12/2022] [Indexed: 12/22/2022] Open
Abstract
Background: The gastrointestinal tract has been speculated to serve as a reservoir for Acinetobacter, however little is known about the ecological fitness of Acinetobacter strains in the gut. Likewise, not much is known about the ability of Acinetobacter to consume dietary, or host derived nutrients or their capacity to modulate host gene expression. Given the increasing prevalence of Acinetobacter in the clinical setting, we sought to characterize how A. calcoaceticus responds to gut-related stressors and identify potential microbe-host interactions. Materials and Methods: To accomplish these aims, we grew clinical isolates and commercially available strains of A. calcoaceticus in minimal media with different levels of pH, osmolarity, ethanol and hydrogen peroxide. Utilization of nutrients was examined using Biolog phenotypic microarrays. To examine the interactions of A. calcoaceticus with the host, inverted murine organoids where the apical membrane is exposed to bacteria, were incubated with live A. calcoaceticus, and gene expression was examined by qPCR. Results: All strains grew modestly at pH 6, 5 and 4; indicating that these strains could tolerate passage through the gastrointestinal tract. All strains had robust growth in 0.1 and 0.5 M NaCl concentrations which mirror the small intestine, but differences were observed between strains in response to 1 M NaCl. Additionally, all strains tolerated up to 5% ethanol and 0.1% hydrogen peroxide. Biolog phenotypic microarrays revealed that A. calcoaceticus strains could use a range of nutrient sources, including monosaccharides, disaccharides, polymers, glycosides, acids, and amino acids. Interestingly, the commercially available A. calcoaceticus strains and one clinical isolate stimulated the pro-inflammatory cytokines Tnf, Kc, and Mcp-1 while all strains suppressed Muc13 and Muc2. Conclusion: Collectively, these data demonstrate that A. calcoaceticus is well adapted to dealing with environmental stressors of the gastrointestinal system. This data also points to the potential for Acinetobacter to influence the gut epithelium.
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Affiliation(s)
- Janiece S. Glover
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Brittney D. Browning
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Taylor D. Ticer
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Amy C. Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Melinda A. Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
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24
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Wan Y, Yang L, Jiang S, Qian D, Duan J. Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis. Inflamm Bowel Dis 2022; 28:639-648. [PMID: 34871402 DOI: 10.1093/ibd/izab277] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.
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Affiliation(s)
- Yue Wan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Lei Yang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Shu Jiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Dawei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
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25
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Gao H, He C, Hua R, Guo Y, Wang B, Liang C, Gao L, Shang H, Xu JD. Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases. Front Mol Biosci 2022; 9:817392. [PMID: 35402506 PMCID: PMC8988245 DOI: 10.3389/fmolb.2022.817392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 12/21/2022] Open
Abstract
The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.
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Affiliation(s)
- Han Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Chengwei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Rongxuan Hua
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yuexin Guo
- Department of Oral Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Boya Wang
- Undergraduate Student of 2018 Eight Program of Clinical Medicine, Peking University Health Science Center, Beijing, China
| | - Chen Liang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lei Gao
- Department of Biomedical Informatics, School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Hongwei Shang
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Jing-Dong Xu,
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26
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Cui Y, Zhou X, Chen L, Tang Z, Mo F, Li XC, Mao H, Wei X, Wang C, Wang H. Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4-CHOP-CHAC1 Signal Pathway in IPEC-J2 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:15495-15511. [PMID: 34919378 DOI: 10.1021/acs.jafc.1c03361] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The intestinal epithelium is susceptible to heat stress (HS), which leads to gut leakage and inflammation. However, the mechanisms underlying HS-induced intestine dysfunction have yet to be elucidated. We established an in vitro chronic heat exposure-induced intestinal injury of intestinal porcine epithelial cells (IPEC-J2) exposed to high temperatures (43 °C) for 12 h. The results revealed that HS increased reactive oxygen species (ROS) generation and decreased superoxide dismutase 2 (SOD2) expression, leading to oxidative stress. Western blotting analysis demonstrated that HS induced apoptosis as evidenced by increased cytochrome c (Cyt c) release in the cytoplasm and caspase 3 activation. Transcriptome sequencing analysis revealed that HS activated the endoplasmic reticulum stress (ERS) response/unfolded protein response (UPR) but inhibited glutathione metabolism. Specifically, HS triggered the pro-apoptotic activating transcription factor 4 (ATF4)/CEBP-homologous protein (CHOP) branch of the UPR. Interestingly, glutathione-specific gamma-glutamylcyclotransferase1 (CHAC1) involved in glutathione degradation was upregulated due to heat exposure and was proved to be downstream of the ATF4-CHOP signal pathway. Knockdown of CHAC1 attenuated the HS-induced decrease in glutathione level and cell apoptosis. These studies suggest that crosstalk between ERS and oxidative stress in HS-induced apoptosis might be dependent on the ATF4-CHOP-CHAC1 signal pathway in IPEC-J2 cells.
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Affiliation(s)
- Yanjun Cui
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Xu Zhou
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Leyi Chen
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Zhining Tang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Fan Mo
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Xiang Chen Li
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Huiling Mao
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Xiaoshi Wei
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Chong Wang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Haifeng Wang
- College of Animal Science, MOE Key Laboratory of Molecular Animal Nutrition, Zhejiang University, Hangzhou 310058, P. R. China
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Bertoli-Avella A, Hotakainen R, Al Shehhi M, Urzi A, Pareira C, Marais A, Al Shidhani K, Aloraimi S, Morales-Torres G, Fisher S, Demuth L, Moteleb Selim LA, Al Menabawy N, Busehail M, AlShaikh M, Gilani N, Chalabi DN, Alharbi NS, Alfadhel M, Abdelrahman M, Venselaar H, Anjum N, Saeed A, Alghamdi MA, Aljaedi H, Arabi H, Karageorgou V, Khan S, Hajjari Z, Radefeldt M, Al-Ali R, Tripolszki K, Jamhawi A, Paknia O, Cozma C, Cheema H, Ameziane N, Al-Muhsen S, Bauer P. A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene. J Med Genet 2021; 59:993-1001. [PMID: 34952832 PMCID: PMC9554030 DOI: 10.1136/jmedgenet-2021-108150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/10/2021] [Indexed: 11/08/2022]
Abstract
Purpose We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. Methods Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. Results We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. Conclusion We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.
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Affiliation(s)
| | - Ronja Hotakainen
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | | | - Alice Urzi
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Catarina Pareira
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Anett Marais
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | | | | | | | - Steffen Fisher
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Laura Demuth
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | | | - Nihal Al Menabawy
- Pediatric Neurology and Metabolic division, Cairo University Childrens Hospital, Cairo, Egypt
| | - Maryam Busehail
- Department of Pediatrics, Salmaniya Medical Complex, Manama, Bahrain
| | - Mohammed AlShaikh
- Department of Pediatrics, Salmaniya Medical Complex, Manama, Bahrain
| | | | | | - Nasser S Alharbi
- Pulmonology Unit, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Majid Alfadhel
- Medical Genomic Research department, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
- Genetics and Precision Medicine department (GPM), King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
| | - Mohammed Abdelrahman
- Immunology Research laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Hanka Venselaar
- Centre for Molecular and Biomolecular Informatics, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, Gelderland, Netherlands
| | - Nadeem Anjum
- Department of Pediatric Gastroenterology, Children's Hospital of Lahore, Lahore, Pakistan
| | - Anjum Saeed
- Department of Pediatric Gastroenterology, Children's Hospital of Lahore, Lahore, Pakistan
| | - Malak Ali Alghamdi
- Medical Genetics Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Hamad Aljaedi
- Department of Pathology, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Hisham Arabi
- Department of Pediatrics, King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
| | | | - Suliman Khan
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Zahra Hajjari
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Mandy Radefeldt
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Ruslan Al-Ali
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | | | - Amer Jamhawi
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Omid Paknia
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Claudia Cozma
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Huma Cheema
- Department of Pediatric Gastroenterology, Children's Hospital of Lahore, Lahore, Pakistan
| | - Najim Ameziane
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
| | - Saleh Al-Muhsen
- Immunology Research laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Peter Bauer
- Medical Reporting & Genomic Research, Centogene GmbH, Rostock, Germany
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28
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Maarouf A, Boissard A, Henry C, Leman G, Coqueret O, Guette C, Lelièvre E. Anterior gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy‑induced senescence escape. Int J Oncol 2021; 60:5. [PMID: 34913074 PMCID: PMC8727137 DOI: 10.3892/ijo.2021.5295] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 11/09/2021] [Indexed: 11/05/2022] Open
Abstract
Among the different chemotherapies available, genotoxic drugs are widely used. In response to these drugs, particularly doxorubicin, tumor cells can enter into senescence. Chemotherapy‑induced senescence (CIS) is a complex response. Long described as a definitive arrest of cell proliferation, the present authors and various groups have shown that this state may not be complete and could allow certain cells to reproliferate. The mechanism could be due to the activation of new signaling pathways. In the laboratory, the proteins involved in these pathways and triggering cell proliferation were studied. The present study determined a new role for anterior gradient protein 2 (AGR2) in vivo in patients and in vitro in a senescence escape model. AGR2's implication in breast cancer patients and proliferation of senescent cells was assessed based on a SWATH‑MS proteomic study of patients' samples and RNA interference technology on cell lines. First, AGR2 was identified and it was found that its concentration is higher in the serum of patients with breast cancer and that this high concentration is associated with metastasis occurrence. An inverse correlation between intratumoral AGR2 expression and the senescence marker p16 was also observed. This observation led to the study of the role of AGR2 in the CIS escape model. In this model, it was found that AGR2 is overexpressed in cells during senescence escape and that its loss considerably reduces this phenomenon. Furthermore, it was shown that the extracellular form of AGR2 stimulated the reproliferation of senescent cells. The power of proteomic analysis based on the SWATH‑MS approach allowed the present study to highlight the mammalian target of rapamycin (mTOR)/AKT signaling pathway in the senescence escape mechanism mediated by AGR2. Analysis of the two signaling pathways revealed that AGR2 modulated RICTOR and AKT phosphorylation. All these results showed that AGR2 expression in sera and tumors of breast cancer patients is a marker of tumor progression and metastasis occurrence. They also showed that its overexpression regulates CIS escape via activation of the mTOR/AKT signaling pathway.
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Affiliation(s)
- Amine Maarouf
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
| | - Alice Boissard
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
| | - Cécile Henry
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
| | - Géraldine Leman
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
| | - Olivier Coqueret
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
| | - Catherine Guette
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
| | - Eric Lelièvre
- Paul Papin ICO Cancer Center, CRCINA, INSERM U1232, Université de Nantes, Université d'Angers, 49055 Angers, France
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29
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Engevik MA, Herrmann B, Ruan W, Engevik AC, Engevik KA, Ihekweazu F, Shi Z, Luck B, Chang-Graham AL, Esparza M, Venable S, Horvath TD, Haidacher SJ, Hoch KM, Haag AM, Schady DA, Hyser JM, Spinler JK, Versalovic J. Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation. Gut Microbes 2021; 13:1-21. [PMID: 33985416 PMCID: PMC8128206 DOI: 10.1080/19490976.2021.1902717] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Endoplasmic reticulum (ER) stress compromises the secretion of MUC2 from goblet cells and has been linked with inflammatory bowel disease (IBD). Although Bifidobacterium can beneficially modulate mucin production, little work has been done investigating the effects of Bifidobacterium on goblet cell ER stress. We hypothesized that secreted factors from Bifidobacterium dentium downregulate ER stress genes and modulates the unfolded protein response (UPR) to promote MUC2 secretion. We identified by mass spectrometry that B. dentium secretes the antioxidant γ-glutamylcysteine, which we speculate dampens ER stress-mediated ROS and minimizes ER stress phenotypes. B. dentium cell-free supernatant and γ-glutamylcysteine were taken up by human colonic T84 cells, increased glutathione levels, and reduced ROS generated by the ER-stressors thapsigargin and tunicamycin. Moreover, B. dentium supernatant and γ-glutamylcysteine were able to suppress NF-kB activation and IL-8 secretion. We found that B. dentium supernatant, γ-glutamylcysteine, and the positive control IL-10 attenuated the induction of UPR genes GRP78, CHOP, and sXBP1. To examine ER stress in vivo, we first examined mono-association of B. dentium in germ-free mice which increased MUC2 and IL-10 levels compared to germ-free controls. However, no changes were observed in ER stress-related genes, indicating that B. dentium can promote mucus secretion without inducing ER stress. In a TNBS-mediated ER stress model, we observed increased levels of UPR genes and pro-inflammatory cytokines in TNBS treated mice, which were reduced with addition of live B. dentium or γ-glutamylcysteine. We also observed increased colonic and serum levels of IL-10 in B. dentium- and γ-glutamylcysteine-treated mice compared to vehicle control. Immunostaining revealed retention of goblet cells and mucus secretion in both B. dentium- and γ-glutamylcysteine-treated animals. Collectively, these data demonstrate positive modulation of the UPR and MUC2 production by B. dentium-secreted compounds.
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Affiliation(s)
- Melinda A. Engevik
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA,CONTACT Melinda A. Engevik Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA
| | - Beatrice Herrmann
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Wenly Ruan
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA,Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, Texas, USA
| | - Amy C. Engevik
- Department of Surgery, Vanderbilt University Medical Center, NashvilleTN, USA
| | - Kristen A. Engevik
- Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Faith Ihekweazu
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA,Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, Texas, USA
| | - Zhongcheng Shi
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA,Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, Texas, USA
| | - Berkley Luck
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | | | - Magdalena Esparza
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Susan Venable
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Thomas D. Horvath
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Sigmund J. Haidacher
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Kathleen M. Hoch
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Anthony M. Haag
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Deborah A. Schady
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - Joseph M. Hyser
- Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA,Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Jennifer K. Spinler
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA,Department of Pathology, Texas Children’s Hospital, Houston, Texas, USA
| | - James Versalovic
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA,Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, Texas, USA
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Chipurupalli S, Samavedam U, Robinson N. Crosstalk Between ER Stress, Autophagy and Inflammation. Front Med (Lausanne) 2021; 8:758311. [PMID: 34805224 PMCID: PMC8602556 DOI: 10.3389/fmed.2021.758311] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/14/2021] [Indexed: 12/23/2022] Open
Abstract
The endoplasmic reticulum (ER) is not only responsible for protein synthesis and folding but also plays a critical role in sensing cellular stress and maintaining cellular homeostasis. Upon sensing the accumulation of unfolded proteins due to perturbation in protein synthesis or folding, specific intracellular signaling pathways are activated, which are collectively termed as unfolded protein response (UPR). UPR expands the capacity of the protein folding machinery, decreases protein synthesis and enhances ER-associated protein degradation (ERAD) which degrades misfolded proteins through the proteasomes. More recent evidences suggest that UPR also amplifies cytokines-mediated inflammatory responses leading to pathogenesis of inflammatory diseases. UPR signaling also activates autophagy; a lysosome-dependent degradative pathwaythat has an extended capacity to degrade misfolded proteins and damaged ER. Thus, activation of autophagy limits inflammatory response and provides cyto-protection by attenuating ER-stress. Here we review the mechanisms that couple UPR, autophagy and cytokine-induced inflammation that can facilitate the development of novel therapeutic strategies to mitigate cellular stress and inflammation associated with various pathologies.
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Affiliation(s)
- Sandhya Chipurupalli
- Cellular-Stress and Immune Response Laboratory, Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
| | - Unni Samavedam
- College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Nirmal Robinson
- Cellular-Stress and Immune Response Laboratory, Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
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31
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Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov 2021; 21:115-140. [PMID: 34702991 DOI: 10.1038/s41573-021-00320-3] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2021] [Indexed: 02/08/2023]
Abstract
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, resulting in activation of the unfolded protein response (UPR) that aims to restore protein homeostasis. However, the UPR also plays an important pathological role in many diseases, including metabolic disorders, cancer and neurological disorders. Over the last decade, significant effort has been invested in targeting signalling proteins involved in the UPR and an array of drug-like molecules is now available. However, these molecules have limitations, the understanding of which is crucial for their development into therapies. Here, we critically review the existing ER stress and UPR-directed drug-like molecules, highlighting both their value and their limitations.
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32
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Cui YJ, Chen LY, Zhou X, Tang ZN, Wang C, Wang HF. Heat stress induced IPEC-J2 cells barrier dysfunction through endoplasmic reticulum stress mediated apoptosis by p-eif2α/CHOP pathway. J Cell Physiol 2021; 237:1389-1405. [PMID: 34661912 DOI: 10.1002/jcp.30603] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 02/06/2023]
Abstract
Heat stress (HS) induced by high ambient temperatures compromises intestinal epithelial cell. However, the underlying mechanisms by which HS causes intestinal barrier dysfunction remain unclear. In this study, we established an in vitro acute-HS-induced intestinal damage using porcine small intestinal epithelial cell (IPEC-J2) that exposed to the high temperatures (43°C) for 2 h. The cell proliferation, apoptosis, tight junction (TJ) barrier integrity and transcriptomic profiles were measured. The results showed that HS decreased cell viability while increased proapoptotic signaling evidenced by Bax/bcl2 ratio, cytochrome C release to cytosol and active-caspase 3 increases (p < 0.01). HS led to decreased transepithelial electrical resistance, increased cell permeability, and downregulated TJ proteins including ZO1, occludin, and claudin 3 (p < 0.05). Transcriptome sequencing and KEGG pathway analysis revealed HS-induced cell cycle arrest and activation of endoplasmic reticulum stress (ERS) response mediated by a critical transcript eif2α and proapoptotic molecule DDIT3 (known as CHOP). Furthermore, inhibition of ERS by 4-phenylbutyrate (4-PBA) administration and knockdown of eif2α and CHOP significantly attenuated IPEC-J2 cells apoptosis (p < 0.05). Transmission electron microscopy analysis suggested that 4-PBA inhibited HS-induced increase in ER lumen diameter, indicating ultrastructural sign of ERS. In addition, HS-induced impairment of TJs was significantly attenuated by 4-PBA (p < 0.05). Collectively, HS induces ERS and activates the p-eif2α/CHOP signaling pathway to impair epithelial barrier integrity through triggering the intestinal epithelial cell apoptosis.
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Affiliation(s)
- Yan-Jun Cui
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Le-Yi Chen
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Xu Zhou
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Zhi-Ning Tang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Chong Wang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Hai-Feng Wang
- College of Animal Science, MOE Key Laboratory of Molecular Animal Nutrition, Zhejiang University, Hangzhou, China
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Yuan SHC, Chang SC, Huang Y, Liu HP. Serum Level of Tumor-Overexpressed AGR2 Is Significantly Associated with Unfavorable Prognosis of Canine Malignant Mammary Tumors. Animals (Basel) 2021; 11:ani11102923. [PMID: 34679944 PMCID: PMC8532596 DOI: 10.3390/ani11102923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/21/2021] [Accepted: 10/07/2021] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Canine malignant mammary tumor (MMT) is a prevalent malignancy in intact female dogs. A current lack of easily accessible tumor biomarkers hinders a timely assessment of the disease outcome. This study reveals that anterior gradient protein 2 (AGR2) is overexpressed in canine MMT tissues, and elevated levels of extracellular AGR2 in sera of MMT dogs are significantly associated with progression and remote metastasis of MMT and an unfavorable overall survival of the patients. Hence, serum eAGR2 level is significantly associated with an adverse outcome of MMT dogs and holds a predictive potential in MMT prognosis. Abstract Canine malignant mammary tumors (MMTs) are prevalent malignancy in intact female dogs with a high incidence of metastasis and recurrence. A current lack of easily accessible tumor biomarkers hinders a timely assessment of the disease outcome. We previously identified anterior gradient protein 2 (AGR2) with higher protein abundance in canine MMT tissues compared with normal counterparts. AGR2 is an endoplasmic reticulum-resident protein disulfide isomerase involved in the regulation of protein processing and also exists extracellularly via secretion to exert pro-oncogenic functions. In the present study, we validated overexpression of AGR2 in canine MMT tissues from 45 dogs using immunohistochemistry and immunoblotting, and assessed serum AGR2 levels in 81 dogs with MMTs and 21 benign cases using a competitive enzyme-linked immunosorbent assay (ELISA). Our data revealed that serum eAGR2 levels are significantly correlated with MMT progression (p = 0.0007) and remote tumor metastasis (p = 0.002). Moreover, elevated levels of serum eAGR2 are associated with an unfavorable overall survival of MMT dogs in later stage (p = 0.0158). Area under the time-dependent ROC curve (AUC) of serum eAGR2 level as a prognostic indicator was 0.839. Collectively, this study uncovered that serum eAGR2 level is significantly associated with an adverse outcome of MMT dogs and holds a predictive potential in MMT prognosis.
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Affiliation(s)
- Stephen Hsien-Chi Yuan
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan; (S.H.-C.Y.); (S.-C.C.)
| | - Shih-Chieh Chang
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan; (S.H.-C.Y.); (S.-C.C.)
| | - Yenlin Huang
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan 33378, Taiwan;
| | - Hao-Ping Liu
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan; (S.H.-C.Y.); (S.-C.C.)
- Correspondence: ; Tel.: +886-4-22840368 (ext. 51)
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Taank Y, Agnihotri N. Understanding the regulation of β-catenin expression and activity in colorectal cancer carcinogenesis: beyond destruction complex. Clin Transl Oncol 2021; 23:2448-2459. [PMID: 34426910 DOI: 10.1007/s12094-021-02686-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/19/2021] [Indexed: 12/24/2022]
Abstract
Aberrant Wnt/β-catenin signaling is central to colorectal cancer carcinogenesis. The well-known potential of targeting the canonical Wnt signaling pathway for the treatment of CRC is largely attributed to the ability of this pathway to regulate various cellular processes such as cell proliferation, metastasis, drug resistance, immune response, apoptosis, and cellular metabolism. However, with the current approach of targeting this pathway, none of the Wnt-targeted agents have been successfully implicated in clinical practice. Instead of using classical approaches to target this pathway, there is a growing need to find new and modified approaches to achieve the same. For this, a better understanding of the regulation of β-catenin, a major effector of the canonical Wnt pathway is a must. The present review addresses the importance of understanding the regulation of β-catenin beyond the destruction complex. Few recently discovered β-catenin regulators such as ZNF281, TTPAL, AGR2, ARHGAP25, TREM2, and TIPE1 showed significant potential in regulating the development of CRC through modulation of the Wnt/β-catenin signaling pathway in both in vitro and in vivo studies. Although the expression and activity of β-catenin is influenced by many protein regulators, the abovementioned proteins not only influence its expression and activation but are also directly involved in the development of CRC and various other solid tumors. Therefore, we hypothesise that focusing the current research on finding the detailed mechanism of action of these regulators may assist in providing with a better treatment approach or improve the current therapeutic regimens.
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Affiliation(s)
- Y Taank
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - N Agnihotri
- Department of Biochemistry, Panjab University, Chandigarh, India.
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de Moraes CL, Cruz E Melo N, Valoyes MAV, Naves do Amaral W. AGR2 and AGR3 play an important role in the clinical characterization and prognosis of basal like breast cancer. Clin Breast Cancer 2021; 22:e242-e252. [PMID: 34462207 DOI: 10.1016/j.clbc.2021.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 07/10/2021] [Accepted: 07/18/2021] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Basal-like Breast Cancer (BLBC) represents an important molecular subtype of breast cancer characterized by an aggressive behavior, molecular pathology poorly understood and a limited treatment. OBJECTIVE We aim to search for molecular differences between non-BLBC and BLBC tumors in order to propose possible diagnostic and prognostic biomarkers using databases. Metodology: Microarray processed data were downloaded from GEO database considering non-BLBC and BLBC. Enrichment analysis was evaluated using GO consortium and Ingenuity, protein-protein interaction, gene Ontology and co-expression analysis using STRING. Gene expression data was extracted using TCGA, METABRIC and Breast Cancer Gene-Expression Miner v4.2 databases. The Survival was evaluated using The Kaplan-Meier plotter. RESULTS Were identified 58 upregulated and 58 downregulated genes enriched in signaling pathways like PDGF, Angiogenesis, Integrin and WNT. AGR2 and AGR3 expression were reduced in BLBC in relation to non-BLBC tumors, patients aged ≤51 years, and with negativity of ER, PR and HER-2 and nodal status. Low expression of AGR2 and AGR3 were associated with worse OS and RFS for all breast cancer cases. But according to the molecular stratification, low AGR2 conferred worst OS in luminal A, worst RFS in BLBC and good OS and RFS in luminal B. High AGR3 conferred worse OS and RFS in BLBC, but low AGR3 attributed worse OS in luminal A. CONCLUSION AGR2 and AGR3 expression were able to differentiate non-BLBC from BLBC. Downregulation of AGR2 and AGR3 was associated with BLBC clinical phenotype. Furthermore, both genes behave different when considering prognosis and molecular stratification.
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Affiliation(s)
- Carolina Leão de Moraes
- Department of Gynaecology and Obstetrics, Faculty of Medicine, Federal University of Goiás, Goiânia, Brazil.
| | - Natália Cruz E Melo
- Department of Gynaecology and Obstetrics, Faculty of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Maira Andrea Valoyes Valoyes
- Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil; Laboratory of Molecular Genetics, Center for Translational Research in Oncology (LIM24), Cancer Institute of Sao Paulo, Sao Paulo, Brazil
| | - Waldemar Naves do Amaral
- Department of Gynaecology and Obstetrics, Faculty of Medicine, Federal University of Goiás, Goiânia, Brazil; Graduate Program in Health Sciences, Faculty of Medicine, Federal University of Goiás, Goiânia, Brazil
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Al-Shaibi AA, Abdel-Motal UM, Hubrack SZ, Bullock AN, Al-Marri AA, Agrebi N, Al-Subaiey AA, Ibrahim NA, Charles AK, Elawad M, Uhlig HH, Lo B. Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2021; 12:1809-1830. [PMID: 34237462 PMCID: PMC8551217 DOI: 10.1016/j.jcmgh.2021.07.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The gastrointestinal epithelium plays a crucial role in maintaining homeostasis with the gut microbiome. Mucins are essential for intestinal barrier function and serve as a scaffold for antimicrobial factors. Mucin 2 (MUC2) is the major intestinal gel-forming mucin produced predominantly by goblet cells. Goblet cells express anterior gradient 2 (AGR2), a protein disulfide isomerase that is crucial for proper processing of gel-forming mucins. Here, we investigated 2 siblings who presented with severe infantile-onset inflammatory bowel disease. METHODS We performed whole-genome sequencing to identify candidate variants. We quantified goblet cell numbers using H&E histology and investigated the expression of gel-forming mucins, stress markers, and goblet cell markers using immunohistochemistry. AGR2-MUC2 binding was evaluated using co-immunoprecipitation. Endoplasmic reticulum (ER) stress regulatory function of mutant AGR2 was examined by expression studies in Human Embryonic Kidney 293T (HEK293T) using tunicamycin to induce ER stress. RESULTS Both affected siblings were homozygous for a missense variant in AGR2. Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. CONCLUSIONS Phenotype-genotype segregation, functional experiments, and the striking similarity of the human phenotype to AGR2-/- mouse models suggest that the AGR2 missense variant is pathogenic. The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease.
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Affiliation(s)
| | | | | | - Alex N Bullock
- Centre for Medicines Discovery, University of Oxford, Oxford, United Kingdom
| | | | | | | | | | | | - Mamoun Elawad
- Department of Gastroenterology, Sidra Medicine, Doha, Qatar
| | - Holm H Uhlig
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre, Oxford, United Kingdom; Department of Pediatrics, University of Oxford, Oxford, United Kingdom
| | - Bernice Lo
- Research Branch, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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Wen J, Mercado GP, Volland A, Doden HL, Lickwar CR, Crooks T, Kakiyama G, Kelly C, Cocchiaro JL, Ridlon JM, Rawls JF. Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine. SCIENCE ADVANCES 2021; 7:eabg1371. [PMID: 34301599 PMCID: PMC8302129 DOI: 10.1126/sciadv.abg1371] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 06/07/2021] [Indexed: 05/02/2023]
Abstract
Bile salt synthesis, secretion into the intestinal lumen, and resorption in the ileum occur in all vertebrate classes. In mammals, bile salt composition is determined by host and microbial enzymes, affecting signaling through the bile salt-binding transcription factor farnesoid X receptor (Fxr). However, these processes in other vertebrate classes remain poorly understood. We show that key components of hepatic bile salt synthesis and ileal transport pathways are conserved and under control of Fxr in zebrafish. Zebrafish bile salts consist primarily of a C27 bile alcohol and a C24 bile acid that undergo multiple microbial modifications including bile acid deconjugation that augments Fxr activity. Using single-cell RNA sequencing, we provide a cellular atlas of the zebrafish intestinal epithelium and uncover roles for Fxr in transcriptional and differentiation programs in ileal and other cell types. These results establish zebrafish as a nonmammalian vertebrate model for studying bile salt metabolism and Fxr signaling.
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Affiliation(s)
- Jia Wen
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Gilberto Padilla Mercado
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Alyssa Volland
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Heidi L Doden
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Colin R Lickwar
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Taylor Crooks
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Genta Kakiyama
- Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Cecelia Kelly
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Jordan L Cocchiaro
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Jason M Ridlon
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA.
- Department of Animal Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Cancer Center of Illinois, Urbana, IL, USA
| | - John F Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA.
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Wang J, Huang J, Huang L. TSPAN1 silencing protects against cerulein-induced pancreatic acinar cell injury via targeting AGR2. Drug Dev Res 2021; 83:158-166. [PMID: 34212407 DOI: 10.1002/ddr.21855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/11/2022]
Abstract
Acute pancreatitis (AP) is an inflammatory gastrointestinal disorder affecting the pancreas. Previous study reported that tetraspanin 1 (TSPAN1) expression was significantly upregulated in the pancreas of AP patients. However, the underlying molecular mechanism of TSPAN1 in the pathogenesis of AP remains unclear. Thus, the aim of the present study was to investigate the potential role of TSPAN1 in development of AP. RT-qPCR was carried out to quantify the relative mRNA levels of TSPAN1 and anterior gradient-2 (AGR2). The CCK-8 assay was used to detect the cell viability. The TUNEL assay was performed to visualize the apoptotic cells. Western blot was performed to determine the expressions of proteins related to endoplasmic reticulum (ER) stress and apoptosis. ELISA kits were adopted to detect the concentration of inflammatory cytokines including TNF-α and IL-6. Finally, immunoprecipitation (IP) was used to verify the interaction between TSPAN1 and AGR2. TSPAN1 was upregulated in serum of AP patients and AP cell models. TSPAN1 silencing promoted the cell proliferation and inhibited inflammatory response in cerulein-induced AR42J cells. Moreover, TSPAN1 induced endoplasmic reticulum stress by binding AGR2. Interestingly, the overexpression of AGR2 abolished the effects of TSPAN1 silencing on cell proliferation and inflammatory response in cerulein-induced AR42J cells. In summary, TSPAN1 silencing protects against cerulein-induced pancreatic acinar cell injury through inhibiting ER stress-mediated by AGR2. Hence, TSPAN1 may serve as a promising therapeutic target for AP treatment.
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Affiliation(s)
- Jing Wang
- Department of Digestive Medicine, Huanggang Central Hospital, Huanggang City, Hubei Province, China
| | - Jing Huang
- Department of Digestive Medicine, Huanggang Central Hospital, Huanggang City, Hubei Province, China
| | - Lili Huang
- Department of Clinical Laboratory, Lishui People's Hospital, Lishui City, Zhejiang Province, China
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Anterior Gradient Protein 2 Promotes Mucosal Repair in Pediatric Ulcerative Colitis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6483860. [PMID: 34055987 PMCID: PMC8149229 DOI: 10.1155/2021/6483860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 05/05/2021] [Indexed: 12/14/2022]
Abstract
Mucosal healing comprises a key goal of ulcerative colitis (UC) treatment. Anterior gradient protein 2 (AGR2) plays an important role in maintaining intestinal homeostasis in UC. However, the role of AGR2 in the repair of mucosal injury is not yet clear. This study is aimed at investigating the expression of AGR2 in the intestinal tissues of children with UC and its role in repairing mucosal injury. Forty UC patients who were hospitalized in the Pediatric Gastroenterology Ward of Shengjing Hospital affiliated with China Medical University between July 1, 2013, and May 31, 2020, and 20 children who had normal colonoscopy results during the same period (control group) made up the study sample. The disease activity of UC was evaluated based on the pediatric ulcerative colitis activity index, and the ulcerative colitis endoscopic index was evaluated according to the Rachmilewitz score. Immunohistochemical staining was employed to examine the differences in AGR2 expression in the intestinal mucosa between groups. The protective effect of AGR2 in a model of tumor necrosis factor-alpha- (TNF-α-) induced intestinal mucosal barrier injury and the underlying molecular mechanism were explored through in vitro experiments. The results showed that compared with the normal control group, UC patients in the remission or active period had significantly higher expression of AGR2 in the intestine. AGR2 expression was positively correlated with Ki67, an intestinal epithelial cell proliferation marker, but negatively correlated with the degree of endoscopic mucosal injury. In an in vitro model, AGR2 overexpression promoted cell proliferation and migration and inhibited TNF-α-induced intestinal epithelial barrier damage by activating yes-associated protein (YAP). Collectively, our study suggests that AGR2 might serve as a valuable biomarker to help assess the condition and mucosal healing status of UC patients. In vitro, AGR2 promoted the repair of intestinal mucosal barrier injury by activating YAP.
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Wottawa F, Bordoni D, Baran N, Rosenstiel P, Aden K. The role of cGAS/STING in intestinal immunity. Eur J Immunol 2021; 51:785-797. [PMID: 33577080 DOI: 10.1002/eji.202048777] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/30/2020] [Accepted: 02/10/2021] [Indexed: 01/07/2023]
Abstract
The gastrointestinal tract is a highly complex microenvironment under constant interaction with potentially harmful pathogens. Inflammatory bowel disease (IBD) is an archetypical inflammatory disease, in which the intestinal epithelium, defective autophagy, endoplasmic reticulum stress and dysbiosis play a key role. Although no risk-mediating gene variants of STING (TMEM173) have been identified so far, several seminal findings have elucidated a novel understanding of STING in the context of acute and chronic inflammation. STING, an endoplasmic reticulum resident adaptor protein binding cyclic dinucleotides, is a main inducer of type I interferons and canonically involved in antiviral and antibacterial immunity. Recent research has shed light on additional features of STING signaling involved in regulating the microbiota, facilitating autophagy, cell death or ER stress. Importantly, an increasing amount of studies suggests a considerable overlap of IBD pathophysiology and features of STING signaling. Since compelling evidence shows dysregulated type I IFNs in IBD, it is prompting to speculate on the hypothetical role of cGAS/STING/type I IFN signaling in IBD. Here, we summarize recent findings about the origin and function of STING signaling in the gastrointestinal tract and evolve the hypothesis that disturbed STING signaling might be profoundly interconnected with the pathophysiology of IBD.
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Affiliation(s)
- Felix Wottawa
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Dora Bordoni
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Nathan Baran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.,Department of Internal Medicine I., Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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Ahmed M, Metwaly A, Haller D. Modeling microbe-host interaction in the pathogenesis of Crohn's disease. Int J Med Microbiol 2021; 311:151489. [PMID: 33676240 DOI: 10.1016/j.ijmm.2021.151489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/19/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Alterations in the gut microbiota structure and function are thought to play an important role in the pathogenesis of Crohn's disease (CD). The rapid advancement of high-throughput sequencing technologies led to the identification of microbiome risk signatures associated with distinct disease phenotypes and progressing disease entities. Functional validation of the identified microbiome signatures is essential to understand the underlying mechanisms of microbe-host interactions. Germfree mouse models are available to study the functional role of disease-conditioning complex gut microbial ecosystems (dysbiosis) or pathobionts (single bacteria) in the pathogenesis of CD-like inflammation. Here, we discuss the clinical and mechanistic relevance and limitations of gnotobiotic mouse models in the context of CD. In addition, we will address the role of diet as an essential external factor modulating microbiome changes, potentially underlying disease initiation and development.
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Affiliation(s)
- Mohamed Ahmed
- Technical University of Munich, Chair of Nutrition and Immunology, School of Life Sciences, 85354 Freising, Germany
| | - Amira Metwaly
- Technical University of Munich, Chair of Nutrition and Immunology, School of Life Sciences, 85354 Freising, Germany
| | - Dirk Haller
- Technical University of Munich, Chair of Nutrition and Immunology, School of Life Sciences, 85354 Freising, Germany; Technical University of Munich, ZIEL Institute for Food & Health, Germany.
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Eugene SP, Reddy VS, Trinath J. Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union. Front Immunol 2020; 11:543022. [PMID: 33324392 PMCID: PMC7723926 DOI: 10.3389/fimmu.2020.543022] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022] Open
Abstract
The intestinal tract encompasses the largest mucosal surface fortified with a fine layer of intestinal epithelial cells along with highly sophisticated network of the lamina propria immune cells that are indispensable to sustain gut homeostasis. However, it can be challenging to uphold homeostasis when these cells in the intestine are perpetually exposed to insults of both endogenous and exogenous origin. The complex networking and dynamic microenvironment in the intestine demand highly functional cells ultimately burdening the endoplasmic reticulum (ER) leading to ER stress. Unresolved ER stress is one of the primary contributors to the pathogenesis of inflammatory bowel diseases (IBD). Studies also suggest that ER stress can be the primary cause of inflammation and/or the consequence of inflammation. Therefore, understanding the patterns of expression of ER stress regulators and deciphering the intricate interplay between ER stress and inflammatory pathways in intestinal epithelial cells in association with lamina propria immune cells contribute toward the development of novel therapies to tackle IBD. This review provides imperative insights into the molecular markers involved in the pathogenesis of IBD by potentiating ER stress and inflammation and briefly describes the potential pharmacological intervention strategies to mitigate ER stress and IBD. In addition, genetic mutations in the biomarkers contributing to abnormalities in the ER stress signaling pathways further emphasizes the relevance of biomarkers in potential treatment for IBD.
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Affiliation(s)
- Sanchez Preethi Eugene
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad, India
| | | | - Jamma Trinath
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad, India
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Shastri S, Shinde T, Perera AP, Gueven N, Eri R. Idebenone Protects against Spontaneous Chronic Murine Colitis by Alleviating Endoplasmic Reticulum Stress and Inflammatory Response. Biomedicines 2020; 8:biomedicines8100384. [PMID: 32998266 PMCID: PMC7601570 DOI: 10.3390/biomedicines8100384] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 12/18/2022] Open
Abstract
Endoplasmic reticulum (ER) stress in intestinal secretory goblet cells has been linked to the development of ulcerative colitis (UC). Emerging evidence suggests that the short chain quinone drug idebenone displays anti-inflammatory activity in addition to its potent antioxidant and mitochondrial electron donor properties. This study evaluated the impact of idebenone in Winnie mice, that are characterized by spontaneous chronic intestinal inflammation and ER stress caused by a missense mutation in the mucin MUC2 gene. Idebenone (200 mg/kg) was orally administered daily to 5-6 weeks old Winnie mice over a period of 21 days. Idebenone treatment substantially improved body weight gain, disease activity index (DAI), colon length and histopathology score. Immunohistochemistry revealed increased expression of MUC2 protein in goblet cells, consistent with increased MUC2 mRNA levels. Furthermore, idebenone significantly reduced the expression of the ER stress markers C/EBP homologous protein (CHOP), activating transcription factor 6 (ATF6) and X-box binding protein-1 (XBP-1) at both mRNA and protein levels. Idebenone also effectively reduced pro-inflammatory cytokine levels in colonic explants. Taken together, these results indicate that idebenone could represent a potential therapeutic approach against human UC by its strong anti-inflammatory activity and its ability to reduce markers of ER stress.
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Affiliation(s)
- Sonia Shastri
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7250, Tasmania, Australia; (T.S.); (A.P.P.)
- Correspondence: (S.S.); (R.E.); Tel.: +61-4-4992-4236 (S.S.); +61-3-6226-5017 (R.E.)
| | - Tanvi Shinde
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7250, Tasmania, Australia; (T.S.); (A.P.P.)
- Centre for Food Innovation, Tasmanian Institute of Agriculture, University of Tasmania, Launceston 7250, Tasmania, Australia
| | - Agampodi Promoda Perera
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7250, Tasmania, Australia; (T.S.); (A.P.P.)
| | - Nuri Gueven
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7005, Tasmania, Australia;
| | - Rajaraman Eri
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7250, Tasmania, Australia; (T.S.); (A.P.P.)
- Correspondence: (S.S.); (R.E.); Tel.: +61-4-4992-4236 (S.S.); +61-3-6226-5017 (R.E.)
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Pian Y, Chai Q, Ren B, Wang Y, Lv M, Qiu J, Zhu M. Type 3 Innate Lymphoid Cells Direct Goblet Cell Differentiation via the LT-LTβR Pathway during Listeria Infection. THE JOURNAL OF IMMUNOLOGY 2020; 205:853-863. [PMID: 32591396 DOI: 10.4049/jimmunol.2000197] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/26/2020] [Indexed: 12/19/2022]
Abstract
As a specialized subset of intestinal epithelial cells (IECs), goblet cells (GCs) play an important role during the antibacterial response via mucin production. However, the regulatory mechanisms involved in GC differentiation and function during infection, particularly the role of immune cell-IEC cross-talk, remain largely unknown. In this study, using Villin∆Ltbr conditional knockout mice, we demonstrate that LTβR, expressed on IECs, is required for GC hyperplasia and mucin 2 (MUC2) expression during Listeria infection for host defense but not homeostatic maintenance in the naive state. Analysis of single gene-deficient mice revealed that the ligand lymphotoxin (LT), but not LIGHT, and type 3 innate lymphoid cells (ILC3s), but not conventional T cells, are required for MUC2-dependent Listeria control. Conditional deficiency of LT in ILC3s further confirmed the importance of LT signals derived from ILC3s. Lack of ILC3-derived LT or IEC-derived LTβR resulted in the defective expression of genes related to GC differentiation but was not correlated with IEC proliferation and cell death, which were found to be normal by Ki-67 and Annexin V staining. In addition, the alternative NF-κB signaling pathway (involving RelB) in IECs was found to be required for the expression of GC differentiation-related genes and Muc2 and required for the anti-Listeria response. Therefore, our data together suggest a previously unrecognized ILC3-IEC interaction and LT-LTβR-RelB signaling axis governing GC differentiation and function during Listeria infection for host defense.
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Affiliation(s)
- Yaya Pian
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Qian Chai
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
| | - Boyang Ren
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; and
| | - Yue Wang
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; and
| | - Mengjie Lv
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Ju Qiu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
| | - Mingzhao Zhu
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; .,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; and
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45
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Shimizu Y, Nakamura K, Yoshii A, Yokoi Y, Kikuchi M, Shinozaki R, Nakamura S, Ohira S, Sugimoto R, Ayabe T. Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn's disease model mice. Life Sci Alliance 2020; 3:3/6/e201900592. [PMID: 32345659 PMCID: PMC7190275 DOI: 10.26508/lsa.201900592] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 04/07/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
This study provides novel insight into Crohn’s disease where α-defensin misfolding resulting from excessive ER stress in Paneth cells induces dysbiosis and disease progression. Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.
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Affiliation(s)
- Yu Shimizu
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan.,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Kiminori Nakamura
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan.,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Aki Yoshii
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan
| | - Yuki Yokoi
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan.,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Mani Kikuchi
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Ryuga Shinozaki
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan
| | - Shunta Nakamura
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan
| | - Shuya Ohira
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan
| | - Rina Sugimoto
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan
| | - Tokiyoshi Ayabe
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Hokkaido, Japan .,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
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Maurel M, Obacz J, Avril T, Ding YP, Papadodima O, Treton X, Daniel F, Pilalis E, Hörberg J, Hou W, Beauchamp MC, Tourneur-Marsille J, Cazals-Hatem D, Sommerova L, Samali A, Tavernier J, Hrstka R, Dupont A, Fessart D, Delom F, Fernandez-Zapico ME, Jansen G, Eriksson LA, Thomas DY, Jerome-Majewska L, Hupp T, Chatziioannou A, Chevet E, Ogier-Denis E. Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO Mol Med 2020; 11:emmm.201810120. [PMID: 31040128 PMCID: PMC6554669 DOI: 10.15252/emmm.201810120] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses.
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Affiliation(s)
- Marion Maurel
- INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", University of Rennes, Rennes, France.,Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.,VIB Department of Medical Protein Research, UGent, Gent, Belgium.,Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Joanna Obacz
- INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", University of Rennes, Rennes, France.,Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Tony Avril
- INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", University of Rennes, Rennes, France.,Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Yong-Ping Ding
- INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France.,Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,APHP Beaujon Hospital Clichy la Garenne, Paris, France
| | - Olga Papadodima
- Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece
| | - Xavier Treton
- INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France.,Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,APHP Beaujon Hospital Clichy la Garenne, Paris, France
| | - Fanny Daniel
- INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France.,Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,APHP Beaujon Hospital Clichy la Garenne, Paris, France
| | - Eleftherios Pilalis
- Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece.,International Centre for Cancer Vaccine Science, Gdansk, Poland
| | - Johanna Hörberg
- Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
| | - Wenyang Hou
- Departments of Anatomy and Cell Biology, Human Genetics, and Pediatrics, McGill University, Montreal, QC, Canada
| | - Marie-Claude Beauchamp
- Departments of Anatomy and Cell Biology, Human Genetics, and Pediatrics, McGill University, Montreal, QC, Canada
| | - Julien Tourneur-Marsille
- INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France.,Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,APHP Beaujon Hospital Clichy la Garenne, Paris, France
| | - Dominique Cazals-Hatem
- INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France.,Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,APHP Beaujon Hospital Clichy la Garenne, Paris, France
| | - Lucia Sommerova
- Regional Centre for Applied Molecular Oncology (RECAMO), Brno, Czech Republic
| | - Afshin Samali
- Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Jan Tavernier
- VIB Department of Medical Protein Research, UGent, Gent, Belgium
| | - Roman Hrstka
- Regional Centre for Applied Molecular Oncology (RECAMO), Brno, Czech Republic
| | - Aurélien Dupont
- Microscopy Rennes Imaging Centre, and Biosit, UMS3480 CNRS, University of Rennes 1, Rennes Cédex, France
| | | | | | - Martin E Fernandez-Zapico
- Division of Oncology Research, Department of Oncology, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Gregor Jansen
- Biochemistry Department, McGill University Life Sciences Complex, Montréal, QC, Canada
| | - Leif A Eriksson
- Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
| | - David Y Thomas
- Biochemistry Department, McGill University Life Sciences Complex, Montréal, QC, Canada
| | - Loydie Jerome-Majewska
- Departments of Anatomy and Cell Biology, Human Genetics, and Pediatrics, McGill University, Montreal, QC, Canada
| | - Ted Hupp
- International Centre for Cancer Vaccine Science, Gdansk, Poland.,Regional Centre for Applied Molecular Oncology (RECAMO), Brno, Czech Republic.,Edinburgh Cancer Research Centre at the Institute of Genetics and Molecular Medicine, Edinburgh University, Edimburgh, UK
| | - Aristotelis Chatziioannou
- Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece .,e-NIOS PC, Kallithea-Athens, Greece
| | - Eric Chevet
- INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", University of Rennes, Rennes, France .,Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Eric Ogier-Denis
- INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France .,Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.,APHP Beaujon Hospital Clichy la Garenne, Paris, France
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47
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Delom F, Mohtar MA, Hupp T, Fessart D. The anterior gradient-2 interactome. Am J Physiol Cell Physiol 2020; 318:C40-C47. [DOI: 10.1152/ajpcell.00532.2018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.
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Affiliation(s)
- Frederic Delom
- University of Bordeaux, ACTION, Bordeaux, France
- Institut National de la Santé et de la Recherche Médicale, Bordeaux, France
- Institut Bergonié, Bordeaux, France
| | - M. Aiman Mohtar
- University Kebangsaan Malaysia, Medical Molecular Biology Institute (UMBI), The National University of Malaysia, Kuala Lumpur, Malaysia
| | - Ted Hupp
- University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, Scotland, United Kingdom
- University of Gdansk, International Centre for Cancer Vaccine Science, Gdansk, Poland
| | - Delphine Fessart
- University of Bordeaux, ACTION, Bordeaux, France
- Institut National de la Santé et de la Recherche Médicale, Bordeaux, France
- Institut Bergonié, Bordeaux, France
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48
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Coleman OI, Haller D. ER Stress and the UPR in Shaping Intestinal Tissue Homeostasis and Immunity. Front Immunol 2019; 10:2825. [PMID: 31867005 PMCID: PMC6904315 DOI: 10.3389/fimmu.2019.02825] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/18/2019] [Indexed: 12/29/2022] Open
Abstract
An imbalance in the correct protein folding milieu of the endoplasmic reticulum (ER) can cause ER stress, which leads to the activation of the unfolded protein response (UPR). The UPR constitutes a highly conserved and intricately regulated group of pathways that serve to restore ER homeostasis through adaptation or apoptosis. Numerous studies over the last decade have shown that the UPR plays a critical role in shaping immunity and inflammation, resulting in the recognition of the UPR as a key player in pathological processes including complex inflammatory, autoimmune and neoplastic diseases. The intestinal epithelium, with its many highly secretory cells, forms an important barrier and messenger between the luminal environment and the host immune system. It is not surprising, that numerous studies have associated ER stress and the UPR with intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this review, we discuss our current understanding of the roles of ER stress and the UPR in shaping immune responses and maintaining tissue homeostasis. Furthermore, the role played by the UPR in disease, with emphasis on IBD and CRC, is described here. As a key player in immunity and inflammation, the UPR has been increasingly recognized as an important pharmacological target in the development of therapeutic strategies for immune-mediated pathologies. We summarize available strategies targeting the UPR and their therapeutic implications. Understanding the balance between homeostasis and pathophysiology, as well as means of manipulating this balance, provides an important avenue for future research.
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Affiliation(s)
- Olivia I Coleman
- Chair of Nutrition and Immunology, Technical University of Munich, Munich, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology, Technical University of Munich, Munich, Germany.,ZIEL - Institute for Food & Health, Technical University of Munich, Munich, Germany
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49
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Worfolk JC, Bell S, Simpson LD, Carne NA, Francis SL, Engelbertsen V, Brown AP, Walker J, Viswanath YK, Benham AM. Elucidation of the AGR2 Interactome in Esophageal Adenocarcinoma Cells Identifies a Redox-Sensitive Chaperone Hub for the Quality Control of MUC-5AC. Antioxid Redox Signal 2019; 31:1117-1132. [PMID: 31436131 DOI: 10.1089/ars.2018.7647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aims: AGR2 is a tissue-restricted member of the protein disulfide isomerase family that has attracted interest because it is highly expressed in a number of cancers, including gastroesophageal adenocarcinoma. The behavior of AGR2 was analyzed under oxidizing conditions, and an alkylation trapping and immunoprecipitation approach were developed to identify novel AGR2 interacting proteins. Results: The data show that AGR2 is induced in esophageal adenocarcinoma, where it participates in redox-responsive, disulfide-dependent complexes. AGR2 preferentially engages with MUC-5 as a primary client and is coexpressed with the acidic mucin in Barrett's esophagus and esophageal adenocarcinoma tissue. Innovation: New partner chaperones for AGR2 have been identified, including peroxiredoxin IV, ERp44, P5, ERp29, and Ero1α. AGR2 interacts with unexpected metabolic enzymes, including aldehyde dehydrogenase (ALDH)3A1, and engages in an alkylation-sensitive association with the autophagy receptor SQSTM1, suggesting a potential mechanism for the postendoplasmic reticulum targeting of AGR2 to mucin granules. Disulfide-driven AGR2 complex formation provides a framework for a limited number of client proteins to interact, rather than for the recruitment of multiple novel clients. Conclusion: The extended AGR2 interactome will facilitate the development of therapeutics to target AGR2/mucin pathways in esophageal cancer and other conditions, including chronic obstructive pulmonary disease.
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Affiliation(s)
- Jack C Worfolk
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Steven Bell
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Lee D Simpson
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Naomi A Carne
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Sarah L Francis
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Vibecke Engelbertsen
- Department of Surgery, James Cook University Hospital, Middlesbrough, United Kingdom
| | - Adrian P Brown
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Julie Walker
- Department of Surgery, James Cook University Hospital, Middlesbrough, United Kingdom
| | | | - Adam M Benham
- Department of Biosciences, Durham University, Durham, United Kingdom
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50
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Min DJ, Zhao Y, Monks A, Palmisano A, Hose C, Teicher BA, Doroshow JH, Simon RM. Identification of pharmacodynamic biomarkers and common molecular mechanisms of response to genotoxic agents in cancer cell lines. Cancer Chemother Pharmacol 2019; 84:771-780. [PMID: 31367787 PMCID: PMC8127867 DOI: 10.1007/s00280-019-03898-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 06/17/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Genotoxic agents (GAs) including cisplatin, doxorubicin, gemcitabine, and topotecan are often used in cancer treatment. However, the response to GAs is variable among patients and predictive biomarkers are inadequate to select patients for treatment. Accurate and rapid pharmacodynamics measures of response can, thus, be useful for monitoring therapy and improve clinical outcomes. METHODS This study focuses on integrating a database of genome-wide response to treatment (The NCI Transcriptional Pharmacodynamics Workbench) with a database of baseline gene expression (GSE32474) for the NCI-60 cell lines to identify mechanisms of response and pharmacodynamic (PD) biomarkers. RESULTS AND CONCLUSIONS Our analysis suggests that GA-induced endoplasmic reticulum (ER) stress may signal for GA-induced cell death. Reducing the uptake of GA, activating DNA repair, and blocking ER-stress induction cooperate to prevent GA-induced cell death in the GA-resistant cells. ATF3, DDIT3, CARS, and PPP1R15A appear as possible candidate PD biomarkers for monitoring the progress of GA treatment. Further validation studies on the proposed intrinsic drug-resistant mechanism and candidate genes are needed using in vivo data from either patient-derived xenograft models or clinical chemotherapy trials.
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Affiliation(s)
- Dong-Joon Min
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA
| | - Yingdong Zhao
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA
| | - Anne Monks
- Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Alida Palmisano
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA
| | - Curtis Hose
- Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Beverly A Teicher
- Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Richard M Simon
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.
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