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Gao T, Zhang H, Xu Y, He G, Ma H, Zheng C, Li L, Cheng F, Dou H, Zhang F, Zhao H, Qiu Z. HIF-1α Enhances Intestinal Injury and Inflammation in Severe Acute Pancreatitis Through NLRP3 Inflammasome Activation. Dig Dis Sci 2025; 70:1813-1823. [PMID: 39998719 DOI: 10.1007/s10620-025-08926-y] [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: 11/27/2024] [Accepted: 02/13/2025] [Indexed: 02/27/2025]
Abstract
BACKGROUND Severe Acute Pancreatitis (SAP) is associated with significant intestinal injury and inflammation. Hypoxia-Inducible Factor-1α (HIF-1α) and NLRP3 inflammasome have been implicated in this process, but their specific roles remain unclear. OBJECTIVE This study aims to elucidate the roles of HIF-1α and NLRP3 in the pathogenesis of SAP and their effects on intestinal injury, barrier function, and inflammatory responses. METHODS A SAP rat model was established, and histological changes were assessed via HE staining. Western blot was used to analyze HIF-1α and NLRP3 expression in intestinal mucosa. The effects of HIF-1α modulation were examined using the activator DMOG and inhibitor BAY87-2243. Immunohistochemistry, ELISA, and TUNEL staining were used to evaluate intestinal barrier function, permeability markers, and apoptosis. RESULTS HIF-1α and NLRP3 expression significantly increased in SAP rats, peaking at 72 h. HIF-1α activation aggravated intestinal injury and barrier dysfunction, decreasing tight junction protein levels and increasing epithelial apoptosis. Enhanced intestinal permeability and elevated pro-inflammatory cytokines were also observed. Furthermore, HIF-1α activation promoted NLRP3 inflammasome assembly, resulting in increased caspase-1 and IL-1β expression. CONCLUSION HIF-1α exacerbates intestinal injury and inflammation in SAP, likely through NLRP3 inflammasome activation. Targeting HIF-1α may offer a potential therapeutic approach for SAP-induced damage and inflammation.
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Affiliation(s)
- Tao Gao
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Huaisheng Zhang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Yuan Xu
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Guosong He
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Huicong Ma
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Chuanming Zheng
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Lei Li
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Feng Cheng
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Hehe Dou
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Fulong Zhang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Heng Zhao
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Zhaolei Qiu
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China.
- Institute of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu, 233004, Anhui, China.
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Chiba N, Ohnishi T, Matsuguchi T. Hypoxia-Inducible Factor 1 Alpha Potentiates Lipopolysaccharide-Induced Expression of IL-13 and IL-33 in Mast Cells Under Hypoxia. Microbiol Immunol 2025; 69:247-255. [PMID: 39945318 DOI: 10.1111/1348-0421.13202] [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: 09/17/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 04/08/2025]
Abstract
Lipopolysaccharide (LPS) is an exacerbating factor for allergic airway inflammation at least partly due to the activation of mast cells (MCs). LPS stimulates MCs to express both pro-inflammatory and type 2 cytokines, among which interleukin (IL)-13 is essential for the generation of allergic diseases. LPS also induces the expression of "alarmins" such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) from various cell types including epithelial cells, and increased serum IL-33 levels were reported to correlate with disease severity of asthma. MCs reside in peripheral tissues where the oxygen concentration is significantly lower than that in the air and further decreased by inflammation and bronchoconstriction in asthma. However, the effects of hypoxia on LPS-induced cytokine expression in MCs have not been fully elucidated. Here we show that LPS induces Il4, Il6, Il13, Il33, Tnf, and Tslp mRNAs in MCs. Notably, hypoxia robustly enhanced expressions of Il13 and Il33, but not the other cytokines in LPS-stimulated MCs. We also found that this promotive effect is dependent on the presence of hypoxia-inducible factor (HIF) 1α protein. Our study will provide new insight on the role of MCs in the LPS-associated pathogenesis of allergic diseases.
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Affiliation(s)
- Norika Chiba
- Department of Oral Biochemistry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Tomokazu Ohnishi
- Department of Oral Biochemistry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Tetsuya Matsuguchi
- Department of Oral Biochemistry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Toskas A, Milias S, Papamitsou T, Meditskou S, Kamperidis N, Sioga A. The role of IL-19, IL-24, IL-21 and IL-33 in intestinal mucosa of inflammatory bowel disease: A narrative review. Arab J Gastroenterol 2025; 26:9-17. [PMID: 38395629 DOI: 10.1016/j.ajg.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/15/2023] [Accepted: 01/03/2024] [Indexed: 02/25/2024]
Abstract
Interleukins are potential therapeutic targets that can alter the prognosis and progression of inflammatory bowel disease (IBD). The roles of IL-6, IL-10, IL-17, and IL-23 have been extensively studied, setting the stage for the development of novel treatments for patients with IBD. Other cytokines have been less extensively studied. Members of the IL-20 family, mainly IL-19 and IL-24, are involved in the pathogenesis of IBD, but their exact role remains unclear. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of colonic Tregs in animal models of colitis and patients with IBD. IL-21 is involved in the Th1, Th2, and Th17 responses. Data support a promising future use of these interleukins as biomarkers of severe diseases and as potential therapeutic targets for novel monoclonal antibodies. This review aims to summarize the existing studies involving animal models of colitis and patients with IBD to clarify their role in the intestinal mucosa.
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Affiliation(s)
- Alexandros Toskas
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece; St Marks Hospital, Watford Rd, Harrow, London, United Kingdom.
| | - Stefanos Milias
- Private Histopathology Laboratory, Ploutonos 27, Thessaloniki, Greece.
| | - Theodora Papamitsou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Soultana Meditskou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | | | - Antonia Sioga
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Ahn JH, da Silva Pedrosa M, Lopez LR, Tibbs TN, Jeyachandran JN, Vignieri EE, Rothemich A, Cumming I, Irmscher AD, Haswell CJ, Zamboni WC, Yu YRA, Ellermann M, Denson LA, Arthur JC. Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease. Cell Host Microbe 2025; 33:71-88.e9. [PMID: 39701098 DOI: 10.1016/j.chom.2024.11.012] [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: 05/09/2024] [Revised: 11/11/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
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Affiliation(s)
- Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marlus da Silva Pedrosa
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lacey R Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Taylor N Tibbs
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joanna N Jeyachandran
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Emily E Vignieri
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Aaron Rothemich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ian Cumming
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
| | - Alexander D Irmscher
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Corey J Haswell
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William C Zamboni
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yen-Rei A Yu
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Melissa Ellermann
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Lee A Denson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Czopik AK, McNamee EN, Vaughn V, Huang X, Bang IH, Clark T, Wang Y, Ruan W, Nguyen T, Masterson JC, Tak E, Frank S, Collins CB, Li H, Rodriguez-Aguayo C, Lopez-Berestein G, Gerich ME, Furuta GT, Yuan X, Sood AK, de Zoeten EF, Eltzschig HK. HIF-2α-dependent induction of miR-29a restrains T H1 activity during T cell dependent colitis. Nat Commun 2024; 15:8042. [PMID: 39271652 PMCID: PMC11399416 DOI: 10.1038/s41467-024-52113-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.
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Affiliation(s)
- Agnieszka K Czopik
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Eóin N McNamee
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
| | - Victoria Vaughn
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Xiangsheng Huang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - In Hyuk Bang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Trent Clark
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yanyu Wang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wei Ruan
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Tom Nguyen
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
| | - Joanne C Masterson
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Gastrointestinal Eosinophilic Disease Program University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Eunyoung Tak
- Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sandra Frank
- Organ Protection Program, Department of Anesthesiology, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
- Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Colm B Collins
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Howard Li
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
| | - Cristian Rodriguez-Aguayo
- Departmental of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gabriel Lopez-Berestein
- Departmental of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark E Gerich
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Glenn T Furuta
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Gastrointestinal Eosinophilic Disease Program University of Colorado Anschutz School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Anil K Sood
- Departmental of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Edwin F de Zoeten
- Mucosal Inflammation Program, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
- Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
| | - Holger K Eltzschig
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Outcomes Research, Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
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Zhu Y, Pan Y, Fan L, Zou M, Liu Y, Hu J, Xia S, Li Y, Dai R, Wu W. Bioinformatics analysis-based mining of potential markers for inflammatory bowel disease and their immune relevance. Transl Cancer Res 2024; 13:3960-3973. [PMID: 39262455 PMCID: PMC11384922 DOI: 10.21037/tcr-24-274] [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: 02/21/2024] [Accepted: 07/07/2024] [Indexed: 09/13/2024]
Abstract
Background The incidence of inflammatory bowel disease (IBD) is increasing every year and is characterized by a prolonged course, frequent relapses, difficulty in curing, and a lack of more efficacious therapeutic biomarkers. The aim of this study was to find key core genes as therapeutic biomarkers for IBD. Methods GSE75214 in Gene Expression Omnibus (GEO) was used as the experimental set. The genes in the top 25% of standard deviation of all samples in the experimental set were subjected to systematic weighted gene co-expression network analysis (WGCNA) to find candidate genes. Then, least absolute shrinkage and selection operator (LASSO) logistic regression was used to further screen the central genes. Finally, the validity of hub genes was verified on GEO dataset GSE179285 using "BiocManager" R package. Results Twelve well-preserved modules were identified in the experimental set using the WGCNA method. Among them, five modules significantly associated with IBD were screened as clinically significant modules, and four candidate genes were screened from these five modules. Then TIMP1, GUCA2B, and HIF1A were screened as hub genes. These hub genes successfully distinguished tumor samples from healthy tissues by artificial neural network algorithm in an independent test set with an area under the working characteristic curve of 0.946 for the subjects. Conclusions IBD differentially expressed gene (DEGs) are involved in immunoregulatory processes. TIMP1, GUCA2B, and HIF1A, as core genes of IBD, have the potential to be therapeutic targets for patients with IBD, and our findings may provide a new outlook on the future treatment of IBD.
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Affiliation(s)
- Yuwen Zhu
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yanbin Pan
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lichao Fan
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Meng Zou
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yingjie Liu
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jiayi Hu
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Shijun Xia
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yue Li
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Ruijie Dai
- Department of Anorectal Surgery, Shenzhen Traditional Chinese Medicine Anorectal Hospital, Shenzhen, China
| | - Wenjiang Wu
- Department of Anorectal Surgery, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
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Di Mattia M, Sallese M, Neri M, Lopetuso LR. Hypoxic Functional Regulation Pathways in the GI Tract: Focus on the HIF-1α and Microbiota's Crosstalk. Inflamm Bowel Dis 2024; 30:1406-1418. [PMID: 38484200 DOI: 10.1093/ibd/izae046] [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: 07/28/2023] [Indexed: 08/02/2024]
Abstract
Hypoxia is an essential gastrointestinal (GI) tract phenomenon that influences both physiologic and pathologic states. Hypoxia-inducible factors (HIFs), the primary drivers of cell adaptation to low-oxygen environments, have been identified as critical regulators of gut homeostasis: directly, through the induction of different proteins linked to intestinal barrier stabilization (ie, adherent proteins, tight junctions, mucins, integrins, intestinal trefoil factor, and adenosine); and indirectly, through the regulation of several immune cell types and the modulation of autophagy and inflammatory processes. Furthermore, hypoxia and HIF-related sensing pathways influence the delicate relationship existing between bacteria and mammalian host cells. In turn, gut commensals establish and maintain the physiologic hypoxia of the GI tract and HIF-α expression. Based on this premise, the goals of this review are to (1) highlight hypoxic molecular pathways in the GI tract, both in physiologic and pathophysiologic settings, such as inflammatory bowel disease; and (2) discuss a potential strategy for ameliorating gut-related disorders, by targeting HIF signaling, which can alleviate inflammatory processes, restore autophagy correct mechanisms, and benefit the host-microbiota equilibrium.
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Affiliation(s)
- Miriam Di Mattia
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Michele Sallese
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Matteo Neri
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Loris Riccardo Lopetuso
- Department of Medicine and Ageing Sciences, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology, Gabriele d'Annunzio University of Chieti-Pescara, Chieti, Italy
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
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Dzhalilova D, Silina M, Tsvetkov I, Kosyreva A, Zolotova N, Gantsova E, Kirillov V, Fokichev N, Makarova O. Changes in the Expression of Genes Regulating the Response to Hypoxia, Inflammation, Cell Cycle, Apoptosis, and Epithelial Barrier Functioning during Colitis-Associated Colorectal Cancer Depend on Individual Hypoxia Tolerance. Int J Mol Sci 2024; 25:7801. [PMID: 39063041 PMCID: PMC11276979 DOI: 10.3390/ijms25147801] [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: 06/13/2024] [Revised: 07/02/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
One of the factors contributing to colorectal cancer (CRC) development is inflammation, which is mostly hypoxia-associated. This study aimed to characterize the morphological and molecular biological features of colon tumors in mice that were tolerant and susceptible to hypoxia based on colitis-associated CRC (CAC). Hypoxia tolerance was assessed through a gasping time evaluation in a decompression chamber. One month later, the animals were experimentally modeled for colitis-associated CRC by intraperitoneal azoxymethane administration and three dextran sulfate sodium consumption cycles. The incidence of tumor development in the distal colon in the susceptible to hypoxia mice was two times higher and all tumors (100%) were represented by adenocarcinomas, while in the tolerant mice, only 14% were adenocarcinomas and 86% were glandular intraepithelial neoplasia. The tumor area assessed on serially stepped sections was statistically significantly higher in the susceptible animals. The number of macrophages, CD3-CD19+, CD3+CD4+, and NK cells in tumors did not differ between animals; however, the number of CD3+CD8+ and vimentin+ cells was higher in the susceptible mice. Changes in the expression of genes regulating the response to hypoxia, inflammation, cell cycle, apoptosis, and epithelial barrier functioning in tumors and the peritumoral area depended on the initial mouse's hypoxia tolerance, which should be taken into account for new CAC diagnostics and treatment approaches development.
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Affiliation(s)
- Dzhuliia Dzhalilova
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
| | - Maria Silina
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
| | - Ivan Tsvetkov
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
| | - Anna Kosyreva
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
- Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Natalia Zolotova
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
| | - Elena Gantsova
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
- Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Vladimir Kirillov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Health of Russian Federation, 117513 Moscow, Russia;
| | - Nikolay Fokichev
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
| | - Olga Makarova
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia; (M.S.); (I.T.); (A.K.); (N.Z.); (E.G.); (N.F.); (O.M.)
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9
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Roy S, Roy S, Halder S, Jana K, Ukil A. Leishmania exploits host cAMP/EPAC/calcineurin signaling to induce an IL-33-mediated anti-inflammatory environment for the establishment of infection. J Biol Chem 2024; 300:107366. [PMID: 38750790 PMCID: PMC11208913 DOI: 10.1016/j.jbc.2024.107366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/03/2024] [Accepted: 05/05/2024] [Indexed: 06/10/2024] Open
Abstract
Host anti-inflammatory responses are critical for the progression of visceral leishmaniasis, and the pleiotropic cytokine interleukin (IL)-33 was found to be upregulated in infection. Here, we documented that IL-33 induction is a consequence of elevated cAMP-mediated exchange protein activated by cAMP (EPAC)/calcineurin-dependent signaling and essential for the sustenance of infection. Leishmania donovani-infected macrophages showed upregulation of IL-33 and its neutralization resulted in decreased parasite survival and increased inflammatory responses. Infection-induced cAMP was involved in IL-33 production and of its downstream effectors PKA and EPAC, only the latter was responsible for elevated IL-33 level. EPAC initiated Rap-dependent phospholipase C activation, which triggered the release of intracellular calcium followed by calcium/calmodulin complex formation. Screening of calmodulin-dependent enzymes affirmed involvement of the phosphatase calcineurin in cAMP/EPAC/calcium/calmodulin signaling-induced IL-33 production and parasite survival. Activated calcineurin ensured nuclear localization of the transcription factors, nuclear factor of activated T cell 1 and hypoxia-inducible factor 1 alpha required for IL-33 transcription, and we further confirmed this by chromatin immunoprecipitation assay. Administering specific inhibitors of nuclear factor of activated T cell 1 and hypoxia-inducible factor 1 alpha in BALB/c mouse model of visceral leishmaniasis decreased liver and spleen parasite burden along with reduction in IL-33 level. Splenocyte supernatants of inhibitor-treated infected mice further documented an increase in tumor necrosis factor alpha and IL-12 level with simultaneous decrease of IL-10, thereby indicating an overall disease-escalating effect of IL-33. Thus, this study demonstrates that cAMP/EPAC/calcineurin signaling is crucial for the activation of IL-33 and in effect creates anti-inflammatory responses, essential for infection.
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Affiliation(s)
- Souravi Roy
- Department of Biochemistry, University of Calcutta, Kolkata, India
| | - Shalini Roy
- Department of Biochemistry, University of Calcutta, Kolkata, India
| | - Satyajit Halder
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Kuladip Jana
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Anindita Ukil
- Department of Biochemistry, University of Calcutta, Kolkata, India.
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10
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Xiao J, Guo X, Wang Z. Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: key clues toward unraveling the mystery. Front Immunol 2024; 15:1385907. [PMID: 38605960 PMCID: PMC11007100 DOI: 10.3389/fimmu.2024.1385907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/13/2024] Open
Abstract
The human intestinal tract constitutes a complex ecosystem, made up of countless gut microbiota, metabolites, and immune cells, with hypoxia being a fundamental environmental characteristic of this ecology. Under normal physiological conditions, a delicate balance exists among these complex "residents", with disruptions potentially leading to inflammatory bowel disease (IBD). The core pathology of IBD features a disrupted intestinal epithelial barrier, alongside evident immune and microecological disturbances. Central to these interconnected networks is hypoxia-inducible factor-1α (HIF-1α), which is a key regulator in gut cells for adapting to hypoxic conditions and maintaining gut homeostasis. Short-chain fatty acids (SCFAs), as pivotal gut metabolites, serve as vital mediators between the host and microbiota, and significantly influence intestinal ecosystem. Recent years have seen a surge in research on the roles and therapeutic potential of HIF-1α and SCFAs in IBD independently, yet reviews on HIF-1α-mediated SCFAs regulation of IBD under hypoxic conditions are scarce. This article summarizes evidence of the interplay and regulatory relationship between SCFAs and HIF-1α in IBD, pivotal for elucidating the disease's pathogenesis and offering promising therapeutic strategies.
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Affiliation(s)
- Jinyin Xiao
- Graduate School, Hunan University of Traditional Chinese Medicine, Changsha, China
- Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Xiajun Guo
- Department of Geriatric, the First People’s Hospital of Xiangtan City, Xiangtan, China
| | - Zhenquan Wang
- Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
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11
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Wang Y, Lai H, Zhang T, Wu J, Tang H, Liang X, Ren D, Huang J, Li W. Mitochondria of intestinal epithelial cells in depression: Are they at a crossroads of gut-brain communication? Neurosci Biobehav Rev 2023; 153:105403. [PMID: 37742989 DOI: 10.1016/j.neubiorev.2023.105403] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/11/2023] [Accepted: 09/20/2023] [Indexed: 09/26/2023]
Abstract
The role of gut dysbiosis in depression is well established. However, recent studies have shown that gut microbiota is regulated by intestinal epithelial cell (IEC) mitochondria, which has yet to receive much attention. This review summarizes the recent developments about the critical role of IEC mitochondria in actively maintaining gut microbiota, intestinal metabolism, and immune homeostasis. We propose that IEC mitochondrial dysfunction alters gut microbiota composition, participates in cell fate, mediates oxidative stress, activates the peripheral immune system, causes peripheral inflammation, and transmits peripheral signals through the vagus and enteric nervous systems. These pathological alterations lead to brain inflammation, disruption of the blood-brain barrier, activation of the hypothalamic-pituitary-adrenal axis, activation of microglia and astrocytes, induction of neuronal loss, and ultimately depression. Furthermore, we highlight the prospect of treating depression through the mitochondria of IECs. These new findings suggest that the mitochondria of IECs may be a newly found important factor in the pathogenesis of depression and represent a potential new strategy for treating depression.
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Affiliation(s)
- Yi Wang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Han Lai
- School of Foreign Languages, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Tian Zhang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Jing Wu
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Huiling Tang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Xuanwei Liang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Dandan Ren
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Jinzhu Huang
- School of Nursing, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China.
| | - Weihong Li
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China.
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12
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Toskas A, Milias S, Delis G, Meditskou S, Sioga A, Papamitsou T. Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study. Diagnostics (Basel) 2023; 13:2185. [PMID: 37443579 DOI: 10.3390/diagnostics13132185] [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: 05/21/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Interleukins are considered to be potential therapeutic targets that can alter the prognosis and disease progression of IBD. IL-21 has proven to be involved in effector Th1, Th2 and Th17 responses. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of the colonic Tregs in animal models of colitis and patients with IBD. In this retrospective study, we have studied the expression of these interleukins, using immunohistochemistry, in 121 patients with moderate to severe IBD before and after treatment with biologics. The results were statistically processed using SPSSTM. Increased IL-21 expression was found in the UC and CD groups versus the controls. The IL-33 expression was found to be increased in the post-treatment UC and CD groups, suggesting a protective role of this interleukin against bowel inflammation. The IL-33 expression post-treatment was reversely correlated with the activity index score in CD patients, suggesting a better response to treatment in patients with higher IL-33 mucosa levels. This is the first immunohistochemical study of the expression of those interleukins in bowel mucosa before and after treatment with biologics. These data support a possibly promising future use of these interleukins as biomarkers of severe disease and response to treatment and as potential therapeutic targets for novel monoclonal antibodies.
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Affiliation(s)
- Alexandros Toskas
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- St Marks Hospital, Watford Rd, Harrow, London HA1 3UJ, UK
| | - Stefanos Milias
- Private Histopathology Laboratory, Ploutonos 27, 54655 Thessaloniki, Greece
| | - Georgios Delis
- Veterinary School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Soultana Meditskou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Antonia Sioga
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Theodora Papamitsou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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13
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Abstract
Inflammatory bowel disease (IBD) is an idiopathic disease of disordered chronic inflammation in the intestines that affects many people across the world. While the disease is still being better characterized, greater progress has been made in understanding the many components that intersect in the disease. Among these components are the many pieces that compose the intestinal epithelial barrier, the various cytokines and immune cells, and the population of microbes that reside in the intestinal lumen. Since their discovery, the hypoxia-inducible factors (HIFs) have been found to play an expansive role in physiology as well as diseases such as inflammation due to their role in oxygen sensing-related gene transcription, and metabolic control. Making use of existing and developing paradigms in the immuno-gastroenterology of IBD, we summarized that hypoxic signaling plays as another component in the status and progression of IBD, which may include possible functions at the origins of inflammatory dysregulation. © 2023 American Physiological Society. Compr Physiol 13:4767-4783, 2023.
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Affiliation(s)
- Michael Morales
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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14
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Zhang M, Tang B, Huang L, Xiong Y, Tu J, Jia Y, Jiang F, Shen L, Luo Q, Ye J. Hypoxia induces the production of epithelial-derived cytokines in eosinophilic chronic rhinosinusitis with nasal polyps. Int Immunopharmacol 2023; 121:110559. [PMID: 37364325 DOI: 10.1016/j.intimp.2023.110559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/06/2023] [Accepted: 06/22/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Hypoxia plays a significant role in the pathogenesis of chronic rhinosinusitis (CRS). However, the role and mechanism of hypoxia in the type 2 immune response in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remain unclear. METHODS The expression of hypoxia-inducible factor-1α (HIF-1α) and epithelial-derived cytokines (EDCs), including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), was detected in nasal polyps via immunohistochemical analysis. The relationship between HIF-1α and EDCs was also elucidated using Pearson's correlation. Moreover, primary human nasal epithelial cells (HNECs) and a mouse model of ECRSwNP were employed to elucidate the role and mechanism of hypoxia in type 2 immune responses. RESULTS HIF-1α, IL-25, IL-33, and TSLP expression levels were upregulated in the non-ECRSwNP and ECRSwNP groups compared with the control group, with the ECRSwNP group having the highest HIF-1α and EDC expression levels. Additionally, HIF-1α was positively correlated with IL-25 and IL-33 in the ECRSwNP group. Meanwhile, treatment with a HIF-1α inhibitor, PX-478, inhibited the hypoxia-induced increase in the mRNA and protein expression of EDCs and type 2 cytokines in HNECs. Similarly, in vivo, PX-478 inhibited EDC expression in the sinonasal mucosa of mice with ECRSwNP. CONCLUSIONS Hypoxia induces EDC expression by upregulating HIF-1α levels, thereby promoting type 2 immune responses and the development of ECRSwNP. Hence, targeting HIF-1α may represent an effective therapeutic strategy for ECRSwNP.
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Affiliation(s)
- Meiping Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; Institute of Jiangxi Otorhinolaryngology Head & Neck Suegery, Nanchang, Jiangxi Province, China
| | - Binxiang Tang
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; Institute of Jiangxi Otorhinolaryngology Head & Neck Suegery, Nanchang, Jiangxi Province, China
| | - Ligui Huang
- The 908th Hospital of Joint Logistics Support Force of PLA, Nanchang, Jiangxi Province, China
| | - Yishan Xiong
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Junhao Tu
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yizhen Jia
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Fan Jiang
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Li Shen
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Qing Luo
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jing Ye
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; Institute of Jiangxi Otorhinolaryngology Head & Neck Suegery, Nanchang, Jiangxi Province, China.
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15
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DeMichele E, Sosnowski O, Buret AG, Allain T. Regulatory Functions of Hypoxia in Host-Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa. Microorganisms 2023; 11:1598. [PMID: 37375100 PMCID: PMC10303274 DOI: 10.3390/microorganisms11061598] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Body tissues are subjected to various oxygenic gradients and fluctuations and hence can become transiently hypoxic. Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the cellular hypoxic response and is capable of modulating cellular metabolism, immune responses, epithelial barrier integrity, and local microbiota. Recent reports have characterized the hypoxic response to various infections. However, little is known about the role of HIF activation in the context of protozoan parasitic infections. Growing evidence suggests that tissue and blood protozoa can activate HIF and subsequent HIF target genes in the host, helping or hindering their pathogenicity. In the gut, enteric protozoa are adapted to steep longitudinal and radial oxygen gradients to complete their life cycle, yet the role of HIF during these protozoan infections remains unclear. This review focuses on the hypoxic response to protozoa and its role in the pathophysiology of parasitic infections. We also discuss how hypoxia modulates host immune responses in the context of protozoan infections.
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Affiliation(s)
- Emily DeMichele
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Olivia Sosnowski
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Andre G. Buret
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Thibault Allain
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
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16
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Akimoto M, Susa T, Okudaira N, Koshikawa N, Hisaki H, Iizuka M, Okinaga H, Takenaga K, Okazaki T, Tamamori-Adachi M. Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway. Proc Natl Acad Sci U S A 2023; 120:e2218033120. [PMID: 37094129 PMCID: PMC10160999 DOI: 10.1073/pnas.2218033120] [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: 10/22/2022] [Accepted: 03/30/2023] [Indexed: 04/26/2023] Open
Abstract
As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.
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Affiliation(s)
- Miho Akimoto
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Takao Susa
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Noriyuki Okudaira
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Nobuko Koshikawa
- Department of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Nitona, Chuoh-ku, Chiba260-8717, Japan
| | - Harumi Hisaki
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Masayoshi Iizuka
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
- Medical Education Center, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Hiroko Okinaga
- Department of Internal Medicine, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Keizo Takenaga
- Department of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Nitona, Chuoh-ku, Chiba260-8717, Japan
| | - Tomoki Okazaki
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Mimi Tamamori-Adachi
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
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17
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Yang L, Wan N, Gong F, Wang X, Feng L, Liu G. Transcription factors and potential therapeutic targets for pulmonary hypertension. Front Cell Dev Biol 2023; 11:1132060. [PMID: 37009479 PMCID: PMC10064017 DOI: 10.3389/fcell.2023.1132060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 03/03/2023] [Indexed: 03/19/2023] Open
Abstract
Pulmonary hypertension (PH) is a refractory and fatal disease characterized by excessive pulmonary arterial cell remodeling. Uncontrolled proliferation and hypertrophy of pulmonary arterial smooth muscle cells (PASMCs), dysfunction of pulmonary arterial endothelial cells (PAECs), and abnormal perivascular infiltration of immune cells result in pulmonary arterial remodeling, followed by increased pulmonary vascular resistance and pulmonary pressure. Although various drugs targeting nitric oxide, endothelin-1 and prostacyclin pathways have been used in clinical settings, the mortality of pulmonary hypertension remains high. Multiple molecular abnormalities have been implicated in pulmonary hypertension, changes in numerous transcription factors have been identified as key regulators in pulmonary hypertension, and a role for pulmonary vascular remodeling has been highlighted. This review consolidates evidence linking transcription factors and their molecular mechanisms, from pulmonary vascular intima PAECs, vascular media PASMCs, and pulmonary arterial adventitia fibroblasts to pulmonary inflammatory cells. These findings will improve the understanding of particularly interactions between transcription factor-mediated cellular signaling pathways and identify novel therapies for pulmonary hypertension.
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Affiliation(s)
- Liu Yang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Naifu Wan
- Department of Vascular & Cardiology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fanpeng Gong
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xianfeng Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lei Feng
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Guizhu Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
- *Correspondence: Guizhu Liu,
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18
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Wang P, Li T, Niu C, Sun S, Liu D. ROS-activated MAPK/ERK pathway regulates crosstalk between Nrf2 and Hif-1α to promote IL-17D expression protecting the intestinal epithelial barrier under hyperoxia. Int Immunopharmacol 2023; 116:109763. [PMID: 36736221 DOI: 10.1016/j.intimp.2023.109763] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 02/04/2023]
Abstract
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
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Affiliation(s)
- Pingchuan Wang
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Tianming Li
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Changping Niu
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Siyu Sun
- ShengJing Hospital of China Medical University, Department of Gastroenterology, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Dongyan Liu
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China.
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19
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Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int J Mol Sci 2023; 24:ijms24032425. [PMID: 36768744 PMCID: PMC9917195 DOI: 10.3390/ijms24032425] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
The gastrointestinal tract (GI) has a unique oxygenation profile. It should be noted that the state of hypoxia can be characteristic of both normal and pathological conditions. Hypoxia-inducible factors (HIF) play a key role in mediating the response to hypoxia, and they are tightly regulated by a group of enzymes called HIF prolyl hydroxylases (PHD). In this review, we discuss the involvement of inflammation hypoxia and signaling pathways in the pathogenesis of inflammatory bowel disease (IBD) and elaborate in detail on the role of HIF in multiple immune reactions during intestinal inflammation. We emphasize the critical influence of tissue microenvironment and highlight the existence of overlapping functions and immune responses mediated by the same molecular mechanisms. Finally, we also provide an update on the development of corresponding therapeutic approaches that would be useful for treatment or prophylaxis of inflammatory bowel disease.
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20
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Tang YY, Wang DC, Wang YQ, Huang AF, Xu WD. Emerging role of hypoxia-inducible factor-1α in inflammatory autoimmune diseases: A comprehensive review. Front Immunol 2023; 13:1073971. [PMID: 36761171 PMCID: PMC9905447 DOI: 10.3389/fimmu.2022.1073971] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/13/2022] [Indexed: 01/26/2023] Open
Abstract
Hypoxia-inducible factor-1α (HIF-1α) is a primary metabolic sensor, and is expressed in different immune cells, such as macrophage, dendritic cell, neutrophil, T cell, and non-immune cells, for instance, synovial fibroblast, and islet β cell. HIF-1α signaling regulates cellular metabolism, triggering the release of inflammatory cytokines and inflammatory cells proliferation. It is known that microenvironment hypoxia, vascular proliferation, and impaired immunological balance are present in autoimmune diseases. To date, HIF-1α is recognized to be overexpressed in several inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and function of HIF-1α is dysregulated in these diseases. In this review, we narrate the signaling pathway of HIF-1α and the possible immunopathological roles of HIF-1α in autoimmune diseases. The collected information will provide a theoretical basis for the familiarization and development of new clinical trials and treatment based on HIF-1α and inflammatory autoimmune disorders in the future.
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Affiliation(s)
- Yang-Yang Tang
- Department of Evidence-Based Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Da-Cheng Wang
- Department of Evidence-Based Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - You-Qiang Wang
- Department of Laboratory Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - An-Fang Huang
- Department of Rheumatology and Immunology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Wang-Dong Xu
- Department of Evidence-Based Medicine, Southwest Medical University, Luzhou, Sichuan, China,*Correspondence: Wang-Dong Xu,
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21
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Alva R, Moradi F, Liang P, Stuart JA. Culture of Cancer Cells at Physiological Oxygen Levels Affects Gene Expression in a Cell-Type Specific Manner. Biomolecules 2022; 12:1684. [PMID: 36421698 PMCID: PMC9688152 DOI: 10.3390/biom12111684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/03/2022] [Accepted: 11/11/2022] [Indexed: 02/26/2024] Open
Abstract
Standard cell culture is routinely performed at supraphysiological oxygen levels (~18% O2). Conversely, O2 levels in most mammalian tissues range from 1-6% (physioxia). Such hyperoxic conditions in cell culture can alter reactive oxygen species (ROS) production, metabolism, mitochondrial networks, and response to drugs and hormones. The aim of this study was to investigate the transcriptional response to different O2 levels and determine whether it is similar across cell lines, or cell line-specific. Using RNA-seq, we performed differential gene expression and functional enrichment analyses in four human cancer cell lines, LNCaP, Huh-7, PC-3, and SH-SY5Y cultured at either 5% or 18% O2 for 14 days. We found that O2 levels affected transcript abundance of thousands of genes, with the affected genes having little overlap between cell lines. Functional enrichment analysis also revealed different processes and pathways being affected by O2 in each cell line. Interestingly, most of the top differentially expressed genes are involved in cancer biology, which highlights the importance of O2 levels in cancer cell research. Further, we observed several hypoxia-inducible factor (HIF) targets, HIF-2α targets particularly, upregulated at 5% O2, consistent with a role for HIFs in physioxia. O2 levels also differentially induced the transcription of mitochondria-encoded genes in most cell lines. Finally, by comparing our transcriptomic data from LNCaP and PC-3 with datasets from the Prostate Cancer Transcriptome Atlas, a correlation between genes upregulated at 5% O2 in LNCaP cells and the in vivo prostate cancer transcriptome was found. We conclude that the transcriptional response to O2 over the range from 5-18% is robust and highly cell-type specific. This latter finding indicates that the effects of O2 levels are difficult to predict and thus highlights the importance of regulating O2 in cell culture.
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Affiliation(s)
- Ricardo Alva
- Department of Biological Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Fereshteh Moradi
- Department of Biological Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Ping Liang
- Department of Biological Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Biotechnology, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Jeffrey A. Stuart
- Department of Biological Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Biotechnology, Brock University, St. Catharines, ON L2S 3A1, Canada
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22
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Abstract
Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Gaelen K. Dwyer
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Louise M. D'Cruz
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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23
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Goodman WA, Basavarajappa SC, Liu AR, Rodriguez FDS, Mathes T, Ramakrishnan P. Sam68 contributes to intestinal inflammation in experimental and human colitis. Cell Mol Life Sci 2021; 78:7635-7648. [PMID: 34693458 PMCID: PMC8817240 DOI: 10.1007/s00018-021-03976-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/29/2021] [Accepted: 10/09/2021] [Indexed: 12/25/2022]
Abstract
Sam68 is an RNA-binding protein with an adaptor role in signal transduction. Our previous work identified critical proinflammatory and apoptotic functions for Sam68, downstream of the TNF/TNFR1 and TLR2/3/4 pathways. Recent studies have shown elevated Sam68 in inflamed tissues from rheumatoid arthritis and ulcerative colitis (UC) patients, suggesting that Sam68 contributes to chronic inflammatory diseases. Here, we hypothesized that deletion of Sam68 is protective against experimental colitis in vivo, via reductions in TNF-associated inflammatory signaling. We used Sam68 knockout (KO) mice to study the role of Sam68 in experimental colitis, including its contributions to TNF-induced inflammatory gene expression in three-dimensional intestinal organoid cultures. We also studied the expression of Sam68 and inflammatory genes in colon tissues of UC patients. Sam68 KO mice treated with an acute course of DSS exhibited significantly less weight loss and histopathological inflammation compared to wild-type controls, suggesting that Sam68 contributes to experimental colitis. Bone marrow transplants showed no pathologic role for hematopoietic cell-specific Sam68, suggesting that non-hematopoietic Sam68 drives intestinal inflammation. Gene expression analyses showed that Sam68 deficiency reduced the expression of proinflammatory genes in colon tissues from DSS-treated mice, as well as TNF-treated three-dimensional colonic organoids. We also found that inflammatory genes, such as TNF, CCR2, CSF2, IL33 and CXCL10, as well as Sam68 protein, were upregulated in inflamed colon tissues of UC patients. This report identifies Sam68 as an important inflammatory driver in response to intestinal epithelial damage, suggesting that targeting Sam68 may hold promise to treat UC patients.
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Affiliation(s)
- Wendy A Goodman
- Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 2103 Cornell Road, Room 6526, Wolstein Research Building, Cleveland, OH, 44106, USA
| | - Shrikanth C Basavarajappa
- Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 2103 Cornell Road, Room 6526, Wolstein Research Building, Cleveland, OH, 44106, USA
| | - Angela R Liu
- Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 2103 Cornell Road, Room 6526, Wolstein Research Building, Cleveland, OH, 44106, USA
| | - Franklin D Staback Rodriguez
- Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 2103 Cornell Road, Room 6526, Wolstein Research Building, Cleveland, OH, 44106, USA
| | - Tailor Mathes
- Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 2103 Cornell Road, Room 6526, Wolstein Research Building, Cleveland, OH, 44106, USA
| | - Parameswaran Ramakrishnan
- Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 2103 Cornell Road, Room 6526, Wolstein Research Building, Cleveland, OH, 44106, USA.
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
- The Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
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24
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Hu J, Yan Q, Jiang H, Xu C, Chen Y, Yuan W. A decrease in IL-33 regulates matrix degradation and apoptosis in intervertebral disc degeneration via HIF-1alpha. Am J Transl Res 2021; 13:12724-12733. [PMID: 34956487 PMCID: PMC8661207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 09/22/2021] [Indexed: 06/14/2023]
Abstract
Low back pain (LBP) is a common aging-associated disease that can cause disability in old people. Previous research revealed that an imbalance in the extracellular matrix (ECM) via abnormal hypoxia-inducible factor-1alpha (HIF-1α) expression in nucleus pulposus (NP) cells was one of the key factors in the pathogenesis of intervertebral disc degeneration (IDD). However, the mechanism by which the ECM is reduced in patients with IDD is not fully understood. Here, we reported that a new member of the interleukin (IL)-1 family, IL-33, was positively correlated with HIF-1α and was decreased in the NP cells of individuals with IDD. IL-33 overexpression in degenerative NP cells decreased the levels of matrix metalloproteinase-3/13 (MMP-3/13), a disintegrin and metallo-proteinase with thrombospondin motifs-4/5 (ADAMTS-4/5), and promoted ECM expression in vitro. Furthermore, we preliminarily explored the antiapoptotic effects of IL-33, which could reduce the expression of Caspase-3 and promote the level of Bcl-2 in degenerative NP cells. Furthermore, when HIF-1α expression was silenced, IL-33-mediated upregulation of ECM expression was weakened. Thus, IL-33-induced HIF-1α upregulation may represent a novel therapeutic strategy to ameliorate IDD in patients with LBP.
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Affiliation(s)
- Jinquan Hu
- Department of Orthopedics, Changzheng Hospital Affiliated with Second Military Medical University415 Fengyang Road, Shanghai 200003, China
| | - Qiang Yan
- Reproductive Medical Center, Shanghai First Maternity and Infant Hospital, Tongji UniversityShanghai 201204, China
| | - Hanran Jiang
- Department of Ophthalmology, Changzheng Hospital Affiliated with Second Military Medical University415 Fengyang Road, Shanghai 200003, China
| | - Chen Xu
- Department of Orthopedics, Changzheng Hospital Affiliated with Second Military Medical University415 Fengyang Road, Shanghai 200003, China
| | - Yu Chen
- Department of Orthopedics, Changzheng Hospital Affiliated with Second Military Medical University415 Fengyang Road, Shanghai 200003, China
| | - Wen Yuan
- Department of Orthopedics, Changzheng Hospital Affiliated with Second Military Medical University415 Fengyang Road, Shanghai 200003, China
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25
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Yin J, Ren Y, Yang K, Wang W, Wang T, Xiao W, Yang H. The role of hypoxia-inducible factor 1-alpha in inflammatory bowel disease. Cell Biol Int 2021; 46:46-51. [PMID: 34658125 DOI: 10.1002/cbin.11712] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/21/2021] [Accepted: 10/08/2021] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) develops as a result of a combination of genetic predisposition, dysbiosis of the gut microbiota, and environmental influences, which is mainly represented by ulcerative colitis (UC) and Crohn's disease (CD). IBDs can result in inflammatory hypoxia by causing intestinal inflammation and vascular damage. The hypoxia-inducible factor 1-alpha (HIF-1α), as a transcription factor, can regulate the cellular adaptation to low oxygen levels and support the development and function of the gut barrier. HIF-αplays its functions through translocating into the nucleus, dimerizing with HIF-1β, and binding to hypoxia-responsive elements of HIF-1 target genes. So far, most studies have addressed the function of HIF-1α in murine models of IBD. In this review, we aim to outline the major roles of HIF-1α in the IBD.
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Affiliation(s)
- Jiuheng Yin
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, China
| | - Yanbei Ren
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, China
| | - Kunqiu Yang
- Department of General Surgery, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Wensheng Wang
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, China
| | - Ting Wang
- Nursing Department, Nursing School of Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Weidong Xiao
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, China
| | - Hua Yang
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, China
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26
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Barbier L, Robin A, Sindayigaya R, Ducousso H, Dujardin F, Thierry A, Hauet T, Girard JP, Pellerin L, Gombert JM, Herbelin A, Salamé E. Endogenous Interleukin-33 Acts as an Alarmin in Liver Ischemia-Reperfusion and Is Associated With Injury After Human Liver Transplantation. Front Immunol 2021; 12:744927. [PMID: 34621275 PMCID: PMC8491545 DOI: 10.3389/fimmu.2021.744927] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 08/30/2021] [Indexed: 12/29/2022] Open
Abstract
Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33–deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.
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Affiliation(s)
- Louise Barbier
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,Department of Digestive Surgery and Liver Transplantation, University Hospital of Tours, Tours, France.,University of Tours, Tours, France
| | - Aurélie Robin
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,University Hospital of Poitiers, Poitiers, France
| | - Rémy Sindayigaya
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,Department of Digestive Surgery and Liver Transplantation, University Hospital of Tours, Tours, France.,University of Tours, Tours, France
| | - Héloïse Ducousso
- INSERM U1082, Poitiers, France.,University Hospital of Poitiers, Poitiers, France.,University of Poitiers, Poitiers, France.,Department of Urology, University Hospital of Poitiers, Poitiers, France
| | - Fanny Dujardin
- Department of Pathology, University Hospital of Tours, Tours, France
| | - Antoine Thierry
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,University Hospital of Poitiers, Poitiers, France.,University of Poitiers, Poitiers, France.,Department of Nephrology, University Hospital of Poitiers, Poitiers, France
| | - Thierry Hauet
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,University Hospital of Poitiers, Poitiers, France.,University of Poitiers, Poitiers, France.,Department of Biochemistry, Pôle BIOSPHARM, University Hospital of Poitiers, Poitiers, France
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Luc Pellerin
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,University of Poitiers, Poitiers, France
| | - Jean-Marc Gombert
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,University Hospital of Poitiers, Poitiers, France.,University of Poitiers, Poitiers, France.,Department of Immunology, University Hospital of Poitiers, Poitiers, France
| | - André Herbelin
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,University of Poitiers, Poitiers, France
| | - Ephrem Salamé
- INSERM U1082, Poitiers, France.,FHU SUPORT, Tours-Poitiers-Limoges, France.,Department of Digestive Surgery and Liver Transplantation, University Hospital of Tours, Tours, France.,University of Tours, Tours, France
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27
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Malkov MI, Lee CT, Taylor CT. Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines. Cells 2021; 10:cells10092340. [PMID: 34571989 PMCID: PMC8466990 DOI: 10.3390/cells10092340] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 12/28/2022] Open
Abstract
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.
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Affiliation(s)
- Mykyta I. Malkov
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; (M.I.M.); (C.T.L.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Chee Teik Lee
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; (M.I.M.); (C.T.L.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Cormac T. Taylor
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; (M.I.M.); (C.T.L.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
- Correspondence:
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28
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Interleukin-33-Enhanced CXCR4 Signaling Circuit Mediated by Carcinoma-Associated Fibroblasts Promotes Invasiveness of Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13143442. [PMID: 34298657 PMCID: PMC8306357 DOI: 10.3390/cancers13143442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/29/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the tumor microenvironment merited further evaluation. To simulate the IL-33-induced autocrine signaling, stable clones of IL-33-overexpressing HNSCC cells were established. Besides well-established IL-33/ST2 and SDF1/CXCR4 (stromal-derived factor 1/C-X-C motif chemokine receptor 4) signaling, the CAF-induced IL-33 upregulated CXCR4 via cancer cell induction of IL-33 self-production. The IL-33-enhanced-CXCR4 regulatory circuit involves SDF1/CXCR4 signaling activation and modulates tumor behavior. An in vivo study confirmed the functional role of IL-33/CXCR4 in tumor initiation and metastasis. The CXCR4 and/or IL-33 blockade reduced HNSCC cell aggressiveness, with attenuated invasions and metastases. Immunohistochemistry confirmed that IL-33 and CXCR4 expression correlated significantly with disease-free survival and IL-33-CXCR4 co-expression predicted a poor outcome. Besides paracrine signaling, the CAF-induced IL-33 reciprocally enhanced the autocrine cancer-cell self-production of IL-33 and the corresponding CXCR4 upregulation, leading to the activation of SDF1/CXCR4 signaling subsequent to cancer progression. Thus, targeting the IL-33-enhanced-CXCR4 regulatory circuit attenuates tumor aggressiveness and provides a potential therapeutic option for improving the prognosis in HNSCC patients.
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29
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Liu N, Chen J, Zhao Y, Zhang M, Piao L, Wang S, Yue Y. Role of the IL-33/ST2 receptor axis in ovarian cancer progression. Oncol Lett 2021; 22:504. [PMID: 33986865 DOI: 10.3892/ol.2021.12765] [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: 04/11/2020] [Accepted: 11/26/2020] [Indexed: 01/02/2023] Open
Abstract
Ovarian cancer remains a significant health problem for women in the world due to its diagnosis at advanced stages of disease and the high mortality rate of patients. To date, ovarian cancer is frequently treated with tumor reduction surgery followed by platinum/paclitaxel-based chemotherapy; however, most patients eventually develop relapsed disease. The mRNA expression levels of interleukin-33 (IL-33) and the suppressor of tumorigenicity 2 (ST2) receptor are significantly upregulated in ovarian cancer tissues and metastatic tumor lesions. In addition, IL-33 and ST2 expression has been associated with a poor overall survival in patients with epithelial ovarian cancer. The IL-33 receptor ST2 is expressed as both a membrane-anchored receptor (ST2L) activated by IL-33, and as a soluble variant that exhibits anti-inflammatory properties. In the present review, the functions of the IL-33/ST2L axis in cells and their aberrant expression levels in ovarian cancer were discussed. In addition, targeting their expression as a novel strategy for the control of ovarian cancer progression was emphasized.
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Affiliation(s)
- Ning Liu
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Jintong Chen
- Department of Cancer Immunology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Yinghua Zhao
- Department of Cancer Immunology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Mingyue Zhang
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Li Piao
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Siqing Wang
- Department of Cancer Immunology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Ying Yue
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
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Lu H, Lin J, Xu C, Sun M, Zuo K, Zhang X, Li M, Huang H, Li Z, Wu W, Feng B, Liu Z. Cyclosporine modulates neutrophil functions via the SIRT6-HIF-1α-glycolysis axis to alleviate severe ulcerative colitis. Clin Transl Med 2021; 11:e334. [PMID: 33634990 PMCID: PMC7882115 DOI: 10.1002/ctm2.334] [Citation(s) in RCA: 60] [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: 10/24/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cyclosporine A (CsA) is routinely used to treat patients with steroid-refractory acute severe ulcerative colitis (ASUC). Here, we studied the underlying mechanisms of CsA-mediated alleviation in ASUC patients. METHODS Neutrophil functions including expression of cytokines, apoptosis, and migration were measured by qRT-PCR, flow cytometry, and Transwell assay. Dynamic changes of glycolysis and tricarboxylic acid (TCA) cycle were measured by a Seahorse extracellular flux analyzer. Gene differences were determined and verified by RNA sequencing, qRT-PCR, and Western blotting. Small interfering RNA and inhibitors were used to knock down Sirtuin 6 (SIRT6) in HL-60 cells and block expression of SIRT6, hypoxia-inducible factor-1α (HIF-1α), and pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) in neutrophils. RESULTS We found that HIF-1α expression and glycolysis significantly increased, while the release of IL-8, myeloperoxidase (MPO) and reactive oxygen species (ROS), the apoptosis, and ability of migration markedly decreased in neutrophils of ASUC patients who responded to CsA (Response group) compared with those who did not respond to CsA (Nonresponse group). We also observed that CsA-induced functional alternation of neutrophils was initiated through suppressing SIRT6 expression, which is responsible for expression of the downstream signaling molecules (e.g., HIF-1α, PFKFB3) and PDK4 ubiquitination, leading to fueling neutrophil glycolysis and TCA cycle. Furthermore, blockage of SIRT6 signaling demonstrated to be the same functional changes as CsA to decrease the migration of neutrophils. CONCLUSIONS The data reveal a novel mechanism of CsA in alleviating ASUC by promoting neutrophil HIF-1α expression and restricting excessive neutrophil activation in a SIRT6-HIF-1α-glycolysis axis, suggesting SIRT6 as a candidate target for maintaining mucosal homeostasis and treating intestinal inflammation.
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Affiliation(s)
- Huiying Lu
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
| | - Jian Lin
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
| | - Chunjin Xu
- Department of GastroenterologyFirst People's Hospital of Shangqiu City Affiliated to Xinxiang Medical UniversityShangqiuChina
| | - Mingming Sun
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
| | - Keqiang Zuo
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
| | - Xiaoping Zhang
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
| | - Mingsong Li
- Department of GastroenterologyThird Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Hailiang Huang
- Analytic and Translational Genetics UnitMassachusetts General HospitalBostonMassachusettsUSA
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
- Broad Institute of Harvard and MITCambridgeMassachusettsUSA
| | - Zhong Li
- Shanghai Cell Therapy GroupShanghaiChina
| | - Wei Wu
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
| | - Baisui Feng
- Department of GastroenterologySecond Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhanju Liu
- Center for IBD ResearchDepartment of GastroenterologyShanghai Tenth People's Hospital of Tongji UniversityShanghaiChina
- Department of GastroenterologySecond Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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Gao HN, Ren FZ, Wen PC, Xie LX, Wang R, Yang ZN, Li YX. Yak milk-derived exosomal microRNAs regulate intestinal epithelial cells on proliferation in hypoxic environment. J Dairy Sci 2021; 104:1291-1303. [PMID: 33246613 DOI: 10.3168/jds.2020-19063] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/08/2020] [Indexed: 01/07/2023]
Abstract
Intestinal epithelial cells (IEC) act as an important intestinal barrier whose function can be impaired upon induction by hypoxia. Although intestinal barrier injuries are preventable by milk-derived exosomal microRNAs (miRNAs), the underlying mechanism remains poorly understood. This study aimed to characterize the effect of yak and cow milk-derived exosomal miRNA on the barrier function of IEC-6 under hypoxic conditions, and explore the mechanism of yak milk exosomal miRNA to relieve the hypoxia stress. First, by Illumina HiSeq 2500 (Illumina Inc., San Diego, CA) sequencing, the miRNA expression was systematically screened, and differential expression of 130 miRNAs was identified with 51 being upregulated and 79 downregulated in yak and cow milk-derived exosomes. Furthermore, the top 20 miRNAs that had a relatively consistent high expression in yak milk exosome were identified, and bta-miR-34a was found to be an effective regulator for alleviating hypoxic injury of IEC-6. In vitro assay of the role of bta-miR-34a on survival of IEC-6 in hypoxia by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) confirmed its effectiveness to significantly increase IEC-6 survival up to 13% for 12 h, and up to 9.5% for 24 h. Investigation on the regulatory relationship between bta-miRNA-34a and the hypoxia-inducible factor/apoptosis signaling pathway provided insights into the possible mechanisms by which bta-miR-34a activated the hypoxia-inducible factor and apoptosis signaling pathway, thus promoting IEC-6 survival. The results of this study suggest an important relationship between miRNA expression and intestine barrier integrity, which facilitated further understanding of the physiological function of yak and cow milk exosomal miRNAs, as well as mechanisms of hypoxia-driven epithelial homeostasis.
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Affiliation(s)
- H N Gao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China
| | - F Z Ren
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China; College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, China
| | - P C Wen
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, China
| | - L X Xie
- Treasure of Tibet Yak Dairy Co. Ltd., Lhasa, 610000, China
| | - R Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Z N Yang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China.
| | - Y X Li
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China.
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Lin J, Li G, Xu C, Lu H, Zhang C, Pang Z, Liu Z. Monocyte Chemotactic Protein 1-Induced Protein 1 Is Highly Expressed in Inflammatory Bowel Disease and Negatively Regulates Neutrophil Activities. Mediators Inflamm 2020; 2020:8812020. [PMID: 33488293 PMCID: PMC7803109 DOI: 10.1155/2020/8812020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/06/2020] [Accepted: 12/09/2020] [Indexed: 01/12/2023] Open
Abstract
Monocyte chemotactic protein 1-induced protein 1 (MCPIP-1) is highly expressed in activated immune cells and plays an important role in negatively regulating immune responses. However, its role in regulating neutrophil functions in the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we found that MCPIP-1 was markedly increased at both the transcriptional and translational levels in inflamed mucosa of IBD patients compared with healthy controls, which was mainly expressed in neutrophils. Interestingly, MG-132, a proteasome inhibitor reducing the degradation of MCPIP-1, further facilitated neutrophils to express MCPIP-1 in vitro. Importantly, MCPIP-1 markedly downregulated the production of ROS, MPO, and proinflammatory cytokines (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α, interleukin-8, and interferon-γ) and suppressed the migration of IBD neutrophils. Consistently, the same functional changes were observed in neutrophils from mice with myeloid-targeted overexpression of MCPIP-1 as MG-132 did. Altogether, these findings suggest that MCPIP-1 plays a negative role in regulating neutrophil activities through suppressing the production of ROS, MPO, and proinflammatory cytokines and inhibiting the migration. MG-132 may partially modulate the function of neutrophils via the induction of MCPIP-1. Therefore, targeting MCPIP-1 or exogenous supplementation of MG-132 may provide a therapeutic approach in the treatment of IBD.
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Affiliation(s)
- Jian Lin
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
- Department of Gastroenterology, Affiliated Hospital of Putian University, Putian, China
| | - Gengfeng Li
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Chunjin Xu
- Department of Gastroenterology, The First People's Hospital of Shangqiu City Affiliated to Xinxiang Medical University, Shangqiu, China
| | - Huiying Lu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Cui Zhang
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Zhi Pang
- Department of Gastroenterology, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Huang R, Mao W, Wang G, Ding J, Sun Y, Gao G, Dong P, Sun Z. Synergistic relationship between TSLP and IL-33/ST2 signaling pathways in allergic rhinitis and the effects of hypoxia. Int Forum Allergy Rhinol 2020; 10:511-520. [PMID: 31922361 DOI: 10.1002/alr.22504] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 11/02/2019] [Accepted: 11/08/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND The World Health Organization (WHO) has noted that allergic diseases are a major health problem of the 21st century. Allergic rhinitis (AR) is a type I allergic disease characterized by nasal mucosa and immune system abnormalities. AR is mediated by various inflammatory cells and is mainly characterized by altered secretion of cytokines. Thymic stromal lymphopoietin (TSLP) and the interleukin-33/stimulation-expressed gene 2 (IL-33/ST2) signaling pathway are cytokines that play pivotal roles in many inflammatory responses and allergic reactions. There have been reports of interactions between the 2 pathways in many diseases. Hypoxia is a common pathologic manifestation of AR. The aim of this study was to explore the relationship and expressions and biologic functions of TSLP and IL-33/ST2 in AR, and also to determine the effects of hypoxia on these cytokines. METHODS The rat nasal mucosal epithelium was obtained from Wistar rats. Cells were cultured in groups under hypoxia and normoxia conditions. Identification of rat nasal epithelial cell (RNEpC) and protein expressions was done by immunohistochemistry and immunofluorescence methods. Cell proliferation and migration were examined using the cell counting kit-8 (CCK-8) and Transwell kit. Detection of apoptosis was tested using a fluorescence apoptosis kit. Enzyme-linked immunoassay (ELISA) and Western blot analysis ELISA were used to measure cell secretion and protein expressions. For these experiments, TSLP was knocked down by lentivirus transfection and IL-33 blocked with its antagonist. RESULTS TSLP, IL-33, and ST2 expressions were significantly higher in nasal mucosa epithelial cells from AR rats than in those from control rats. Hypoxia further promoted their expression. Increased TSLP and IL-33/ST2 promoted cell proliferation, inhibited cell apoptosis, and enhanced cell migration. In addition, the downregulation of TSLP expression effectively attenuated expression of the IL-33/ST2 axis and, through use of IL-33 antagonists, could also reduce TSLP expression, a synergistic effect more obvious under hypoxia. CONCLUSION Our data indicate that TSLP and IL-33/ST2 signaling pathways interact with each other in the pathogenesis and pathologic development of AR. TSLP inhibition is a key factor in AR treatment. Inhibiting hypoxia-induced pathologic processes could represent a therapeutic effect by inhibiting IL-33/ST2 expression via downregulating TSLP.
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Affiliation(s)
- Ruofei Huang
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Wei Mao
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Guoliang Wang
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Jian Ding
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Ying Sun
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Gang Gao
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Ping Dong
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
| | - Zhenfeng Sun
- Division of ENT, Key Laboratory of Head and Neck, Shanghai General Hospital of Nanjing Medical University, Shanghai, PR China
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Chen Y, Zuo J, Chen W, Yang Z, Zhang Y, Hua F, Shao L, Li J, Chen Y, Yu Y, Shen Z. The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction. Stem Cell Res Ther 2019; 10:295. [PMID: 31547872 PMCID: PMC6757387 DOI: 10.1186/s13287-019-1392-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/01/2019] [Accepted: 08/19/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats. METHODS AND RESULTS First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats. CONCLUSION These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections. IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.
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Affiliation(s)
- Yueqiu Chen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Jianfeng Zuo
- Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China.,Nantong First People's Hospital, Nantong, China
| | - Weiqian Chen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Ziying Yang
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yanxia Zhang
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Fei Hua
- Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Lianbo Shao
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Jingjing Li
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yunsheng Yu
- Institute for Cardiovascular Science, Soochow University, Suzhou, China. .,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China.
| | - Zhenya Shen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China. .,Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China.
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35
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Liu L, Mao L, Wu X, Wu T, Liu W, Yang Y, Zhang T, Xu Y. BRG1 regulates endothelial-derived IL-33 to promote ischemia-reperfusion induced renal injury and fibrosis in mice. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2551-2561. [DOI: 10.1016/j.bbadis.2019.06.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 05/30/2019] [Accepted: 06/17/2019] [Indexed: 02/07/2023]
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36
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Sun L, Li T, Tang H, Yu K, Ma Y, Yu M, Qiu Y, Xu P, Xiao W, Yang H. Intestinal Epithelial Cells-Derived Hypoxia-Inducible Factor-1α Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes. Front Immunol 2019; 10:806. [PMID: 31040849 PMCID: PMC6476974 DOI: 10.3389/fimmu.2019.00806] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 03/26/2019] [Indexed: 12/18/2022] Open
Abstract
Hif-1α is a master regulator which involved in the transcriptional regulation of anti-inflammatory or cellular responding to hypoxia. Previous work shows that the absence of Hif-1α results in the destruction of intestinal epithelial cell (IEC) and abnormalities of intestinal barrier function. However, we know very little about other functions of Hif-1α on intestinal intraepithelial lymphocyte (IEL). Therefore, we generated a transgenic mouse (Hif1-αΔIEC mice), which was knocked out Hif1-α specifically in IECs, to study the effect of Hif1-α on IEL. IELs were isolated from the small intestine and colon of mice, respectively, and examined by flow cytometry and quantitative real-time PCR. All the cytokines expression was detected by quantitative real-time PCR. The NSAID enteropathy was induced by gavaged with 5 mg/kg indomethacin and the experimental colitis was induced by administration of 2.5% DSS. We found that the number of IELs is increased in Hif1-α ΔIEC mice. It is showed that knockout of Hif1-α in IECs led to significant changes in IEL phenotype, including a marked decline in the CD8αα+ and TCRγδ+ population. The reduction of CD8αα+ IELs is accompanied by increased apoptosis, decreased proliferation and weakened migration in Hif1-αΔIEC mice. Moreover, absence of intestinal epithelial Hif1-α markedly changed the population of IELs in NSAID-induced small intestinal injury and increased susceptibility to dextran sulfate sodium-induced colitis. In summary, our results first time demonstrate that IEC-derived Hif1-α is essential for maintaining IELs homeostasis and intestinal microbiota.
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Affiliation(s)
- Lihua Sun
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Teming Li
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Hanlin Tang
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Kun Yu
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yuanhang Ma
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Min Yu
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yuan Qiu
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Pengyuan Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Weidong Xiao
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Hua Yang
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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Gao HN, Guo HY, Zhang H, Xie XL, Wen PC, Ren FZ. Yak-milk-derived exosomes promote proliferation of intestinal epithelial cells in an hypoxic environment. J Dairy Sci 2018; 102:985-996. [PMID: 30580945 DOI: 10.3168/jds.2018-14946] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 10/02/2018] [Indexed: 12/18/2022]
Abstract
Intestinal epithelial cells (IEC) are an important part of the intestinal barrier. Barrier function was disrupted under hypoxia, but milk-derived exosomes can regulate the intestinal barrier function. However, the mechanisms underlying the association between yak milk exosomes and hypoxia in IEC remain poorly understood. In this follow-up study, we proposed an effective optimization method for purifying yak-milk-derived exosomes. The Western blot analyses indicated that the expression of the proteins of the endosomal sorting complexes required for transport (TSG101), proteins of the tetraspanin family (CD63), and heat shock protein 70 (Hsp-70) proteins from yak-milk-derived exosomes were significantly higher than those in cow-milk-derived exosomes. Flow cytometry analysis showed that yak milk had 3.7 times the number of exosomes compared with cow milk. Moreover, we explored whether yak milk exosomes could facilitate intestinal cell survival under hypoxic conditions in vitro. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide results showed that yak-milk-derived exosomes significantly increased survival of IEC-6 cells with rates of up to 29% for cells incubated in hypoxic conditions for 12 h, compared with those of cow-milk-derived exosomes posttreatment (rates of up to 22% for cells incubated in hypoxic conditions for 12 h). Confocal microscopy revealed that the IEC-6 cells uptake more yak-milk-derived exosomes than cow milk in hypoxic conditions. Furthermore, the Western blot analyses indicated that yak-milk-derived exosomes significantly promote oxygen-sensitive prolyl hydroxylase (PHD)-1 expression and decrease the expression of hypoxia-inducible factor-α and its downstream target vascular endothelial growth factor (VEGF) in the IEC-6 cells. Further, yak-milk-derived exosomes significantly inhibited p53 levels. In conclusion, our findings demonstrate that yak-milk-derived exosomes more effectively activate the hypoxia-inducible factor signaling pathway, thus promoting IEC-6 cell survival, which may result in higher hypoxia tolerance than cow-milk-derived exosomes.
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Affiliation(s)
- H N Gao
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, China; Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - H Y Guo
- Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100094, China
| | - H Zhang
- Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100094, China
| | - X L Xie
- Treasure of Tibet Yak Dairy Co., Ltd., Lhasa, 610000, China
| | - P C Wen
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, China.
| | - F Z Ren
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, China; Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100094, China.
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Watts ER, Walmsley SR. Inflammation and Hypoxia: HIF and PHD Isoform Selectivity. Trends Mol Med 2018; 25:33-46. [PMID: 30442494 DOI: 10.1016/j.molmed.2018.10.006] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/16/2022]
Abstract
Cells sense and respond to hypoxia through the activity of the transcription factor HIF (hypoxia-inducible factor) and its regulatory hydroxylases, the prolyl hydroxylase domain enzymes (PHDs). Multiple isoforms of HIFs and PHDs exist, and isoform-selective roles have been identified in the context of the inflammatory environment, which is itself frequently hypoxic. Recent advances in the field have highlighted the complexity of this system, particularly with regards to the cell and context-specific activity of HIFs and PHDs. Because novel therapeutic agents which regulate this pathway are nearing the clinic, understanding the role of HIFs and PHDs in inflammation outcomes is an essential step in avoiding off-target effects and, crucially, in developing new anti-inflammatory strategies.
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Affiliation(s)
- Emily R Watts
- The University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Sarah R Walmsley
- The University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
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39
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Nanini HF, Bernardazzi C, Castro F, de Souza HSP. Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. World J Gastroenterol 2018; 24:4622-4634. [PMID: 30416310 PMCID: PMC6224468 DOI: 10.3748/wjg.v24.i41.4622] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/08/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
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Affiliation(s)
- Hayandra Ferreira Nanini
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Fernando Castro
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ 22281-100, Brazil
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Khare S, Gokulan K, Williams K, Bai S, Gilbert KM, Blossom SJ. Irreversible effects of trichloroethylene on the gut microbial community and gut-associated immune responses in autoimmune-prone mice. J Appl Toxicol 2018; 39:209-220. [PMID: 30187502 DOI: 10.1002/jat.3708] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/02/2018] [Accepted: 07/06/2018] [Indexed: 12/16/2022]
Abstract
The developing immune system is particularly sensitive to immunotoxicants. This study assessed trichloroethylene (TCE)-induced effects on the gut microbiome and cytokine production during the development in mice. Mice were exposed to TCE (0.05 or 500 μg/mL) at the levels that approximate to environmental or occupational exposure, respectively. Mice were subjected to a continuous developmental exposure to these doses encompassing gestation, lactation and continuing directly in the drinking water postnatally for 154 days (PND154) or PND259. To observe persistence of the effect TCE was removed from the drinking water in a subset of mice on PND154 and were provided regular drinking water until the study terminus (PND259). Abundance of total tissue-associated bacteria reduced only in mice exposed to TCE until PND259. The ratio of Firmicutes/Bacteroidetes did not alter during this continuos exposure; however, cessation of high-dose TCE at PND154 resulted in the increased abundance Bacteroidetes at PND259. Furthermore, high-dose TCE exposure until PND259 resulted in a lower abundance of the genera Bacteroides and Lactobaccilus and increased abundance of genus Bifidobactrium and bacterial family Enterobacteriaceae. TCE exposure until PND154 showed significant changes in the production of interleukin-33; that might play a dual role in maintaining the balance and homeostasis between commensal microbiota and mucosal health. At PND259, interleukin-3, granulocyte-macrophage colony-stimulating factor and Eotaxin were altered in both, the continuous exposure and cessation groups, whereas only a cessation group had a higher level of KC that may facilitate infiltration of neutrophils. The irreversible effects of TCE after a period of exposure cessation suggested a unique programming and potential toxicity of TCE even at the environmental level exposure.
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Affiliation(s)
- Sangeeta Khare
- Division of Microbiology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Kuppan Gokulan
- Division of Microbiology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Katherine Williams
- Division of Microbiology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Shasha Bai
- University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| | - Kathleen M Gilbert
- University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
| | - Sarah J Blossom
- University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
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Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease. Gastroenterol Res Pract 2018; 2018:7192646. [PMID: 30026758 PMCID: PMC6031203 DOI: 10.1155/2018/7192646] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/08/2018] [Indexed: 12/11/2022] Open
Abstract
Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies.
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Liu J, Wang W, Wang L, Chen S, Tian B, Huang K, Corrigan CJ, Ying S, Wang W, Wang C. IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells. EBioMedicine 2018; 33:196-210. [PMID: 29921553 PMCID: PMC6085568 DOI: 10.1016/j.ebiom.2018.06.003] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/03/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022] Open
Abstract
IL-33 may play a role in the vascular remodelling of hypoxic pulmonary hypertension (PH) but the precise mechanisms are still unclear. We hypothesized that hypoxia promotes expression of IL-33 and its receptor ST2 on vascular endothelial cells, which in turn leads to dysfunction of vascular endothelial cells and smooth muscle cells contributing to PH. Immunohistochemistry showed that immunoreactivity for IL-33 and ST2 was significantly increased in lung tissue of murine model of hypoxia-induced PH (HPH) and of subjects with bronchiectasis-PH. trans-Thoracic echocardiography showed that haemodynamic changes and right ventricular hypertrophy associated with HPH were significantly abrogated in St2−/− compared with WT mice. Administration of IL-33 further exacerbated these changes in the hypoxia-exposed WT mice. In vitro, hypoxia significantly increased IL-33/ST2 expression by human pulmonary arterial endothelial cells (HPAECs), while exogenous IL-33 enhanced proliferation, adhesiveness and spontaneous angiogenesis of HPAECs. Knockdown of endogenous Il33 or St2 using siRNA transfection significantly suppressed these effects in both normoxic and hypoxic culture-conditions. Deletion of the St2 gene attenuated hypoxia-induced, elevated lung expression of HIF-1α/VEGFA/VEGFR-2/ICAM-1, while administration of exogenous VEGFA partially reversed the attenuation of the haemodynamic indices of PH. Correspondingly, knockdown of the St2 or Hif1α genes almost completely abrogated IL-33-induced expression of HIF-1α/VEGFA/VEGFR-2 by HPAECs in vitro. Further, IL-33-induced angiogenesis by HPAECs was extensively abrogated by knockdown of the Hif1α/Vegfa or Vegfr2 genes. These data suggest that hypoxia induces elevated expression of IL-33/ST2 by HPAECs which, at least partly by increasing downstream expression of HIF-1α and VEGF initiates vascular remodelling resulting in HPH.
Evidence before this study We have been focusing on the role of cytokines in the pathogenesis of chronic pulmonary diseases for a long time, including asthma, COPD, fibrosis and bronchiectasis. We and others found that IL-33 might contribute to the occurrence and prognosis of many other diseases through binding its receptor ST2. Based on these findings, we were very eager to know whether IL-33/ST2 axis also exerts a role in hypoxia-induced pulmonary hypertension (HPH), a complication of many chronic respiratory diseases. Although it is well known that HIF-1α and VEGF play critical role in this complication, it is still unclear what the upstream of HIF-1α and VEGF is. Therefore, we first tested immunoreactivity for IL-33 and its receptor ST2 in the lung tissue sections derived from surgical specimens and from our established murine models of HPH. Surprisingly, we noted the increased immunoreactivity for both targets in these tissue sections. These findings inspired us to further explore the details of IL-33/ST2 in the pathogenesis of HPH. Added value of this study HPH is a life-threatening complication because there is lack of effective treatment. Although pulmonary arteries and ventricular remodelling might be mainly involved in the pathogenesis of the disease, the precise mechanisms are largely unknown. In the present study, we showed that hypoxia is a critical driver which induced expression of IL-33 and ST2 by endothelial cells. These factors, in turn triggered expression of HIF-1α and VEGF by endothelial cells and led to proliferation, adhesion and tube formation of these cells. We also showed that in the presence of IL-33, endothelial cells were able to affect proliferation and migration of artery smooth muscle cells, although IL-33 alone did not have such effects. These findings suggest that hypoxia and IL-33/ST2 might be initiators for HPH, through regulating downstream factors HIF-1α and VEGF. Implications of all the available evidence Our data suggest that IL-33/ST2 axis plays critical role in the pathogenesis of hypoxia-induced pulmonary hypertension because depletion of these molecules much remitted the phenomenon of complication. These observations might provide alternative therapeutic strategy for clinical treatment of HPH.
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Affiliation(s)
- Jie Liu
- The Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; The Department of Physiology and Pathological Physiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Wang Wang
- The Department of Physiology and Pathological Physiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lei Wang
- The Department of Physiology and Pathological Physiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shihao Chen
- The Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Bo Tian
- Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Capital Medical University & Beijing Institute of Respiratory Medicine, Beijing, China
| | - Kewu Huang
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University & Beijing Institute of Respiratory Medicine, Beijing, China
| | - Chris J Corrigan
- Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation Biology, Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, UK
| | - Sun Ying
- The Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Wei Wang
- The Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
| | - Chen Wang
- The Department of Respirology, Capital Medical University, Beijing, China
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Akimoto M, Takenaga K. Role of the IL-33/ST2L axis in colorectal cancer progression. Cell Immunol 2018; 343:103740. [PMID: 29329638 DOI: 10.1016/j.cellimm.2017.12.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 12/21/2017] [Accepted: 12/28/2017] [Indexed: 12/14/2022]
Abstract
Interleukin-33 (IL-33) has been identified as a natural ligand of ST2L. IL-33 primarily acts as a key regulator of Th2 responses through binding to ST2L, which is antagonized by soluble ST2 (sST2). The IL-33/ST2L axis is involved in various inflammatory pathologies, including ulcerative colitis (UC). Several recent investigations have also suggested that the IL-33/ST2L axis plays a role in colorectal cancer (CRC) progression. In CRC, tumor- and stroma-derived IL-33 may activate ST2L on various cell types in an autocrine and paracrine manner. Although several findings support the hypothesis that the IL-33/ST2L axis positively regulates CRC progression, other reports do not; hence, this hypothesis remains controversial. At any rate, recent studies have provided overwhelming evidence that the IL-33/ST2L axis plays important roles in CRC progression. This review summarizes the role of the IL-33/ST2L axis in the UC and CRC microenvironments.
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Affiliation(s)
- Miho Akimoto
- Department of Life Science, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan
| | - Keizo Takenaga
- Department of Life Science, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan.
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Sun Z, Chang B, Gao M, Zhang J, Zou Z. IL-33-ST2 Axis in Liver Disease: Progression and Challenge. Mediators Inflamm 2017; 2017:5314213. [PMID: 29180837 PMCID: PMC5664344 DOI: 10.1155/2017/5314213] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/20/2017] [Indexed: 12/16/2022] Open
Abstract
The new member of the IL-1 family, interleukin-33 (IL-33), participates in the progression of a variety of diseases through binding with its receptor ST2. Recently, much clinical evidence and experimental data have indicated that IL-33 is associated with various liver diseases. This review primarily addresses the relationship between IL-33 and several hepatic diseases. IL-33 can alleviate high-fat diet- (HFD-) induced hepatic steatosis and insulin resistance, and IL-33 acts as an alarmin, which quickly triggers the immune system to respond to virus invasion and toxic damage to the liver. However, when liver injury is chronic, IL-33 promotes Th2 reactions and hepatic stellate cell (HSC) activity, facilitating progression to liver fibrosis. The complicated functions of IL-33 should be considered before its clinical application.
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Affiliation(s)
- Zijian Sun
- Center of Non-Infectious Liver Diseases, Peking University 302 Clinical Medical School, Beijing, China
| | - Binxia Chang
- Center of Non-Infectious Liver Diseases, Beijing 302 Hospital, Beijing, China
| | - Miaomiao Gao
- Center of Non-Infectious Liver Diseases, Peking University 302 Clinical Medical School, Beijing, China
| | - Jiyuan Zhang
- Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - Zhengsheng Zou
- Center of Non-Infectious Liver Diseases, Peking University 302 Clinical Medical School, Beijing, China
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