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Sun Y, Sun Z, Fang B, Wang R, Liu Y, Li J, Lan H, Zhao W, Hung WL, Zhang M. Exploring the anti-inflammatory potential of Lacticaseibacillus paracasei postbiotics: Mechanistic insights and functional components. FOOD BIOSCI 2025; 65:106105. [DOI: 10.1016/j.fbio.2025.106105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
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2
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Aebisher D, Bartusik-Aebisher D, Przygórzewska A, Oleś P, Woźnicki P, Kawczyk-Krupka A. Key Interleukins in Inflammatory Bowel Disease-A Review of Recent Studies. Int J Mol Sci 2024; 26:121. [PMID: 39795980 PMCID: PMC11719876 DOI: 10.3390/ijms26010121] [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: 11/24/2024] [Revised: 12/19/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025] Open
Abstract
Inflammatory bowel disease (IBD) is an immune disorder of the gastrointestinal tract with a complex aetiopathogenesis, whose development is influenced by many factors. The prevalence of IBD is increasing worldwide, in both industrialized and developing countries, making IBD a global health problem that seriously affects quality of life. In 2019, there were approximately 4.9 million cases of IBD worldwide. Such a large number of patients entails significant healthcare costs. In the treatment of patients with IBD, the current therapeutic target is mucosal healing, as intestinal inflammation often persists despite resolution of abdominal symptoms. Treatment strategies include amino salicylates, corticosteroids, immunosuppressants, and biologic therapies that focus on reducing intestinal mucosal inflammation, inducing and prolonging disease remission, and treating complications. The American College of Gastroenterology (ACG) guidelines also indicate that nutritional therapies may be considered in addition to other therapies. However, current therapeutic approaches are not fully effective and are associated with various limitations, such as drug resistance, variable efficacy, and side effects. As the chronic inflammation that accompanies IBD is characterized by infiltration of a variety of immune cells and increased expression of a number of pro-inflammatory cytokines, including IL-6, TNF-α, IL-12, IL-23 and IFN-γ, new therapeutic approaches are mainly targeting immune pathways. Interleukins are one of the molecular targets in IBD therapy. Interleukins and related cytokines serve as a means of communication for innate and adaptive immune cells, as well as nonimmune cells and tissues. These cytokines play an important role in the pathogenesis and course of IBD, making them promising targets for current and future therapies. In our work, we review scientific studies published between January 2022 and November 2024 describing the most important interleukins involved in the pathogenesis of IBD. Some of the papers present new data on the precise role that individual interleukins play in IBD. New clinical data have also been provided, particularly on blocking interleukin 23 and interleukin 1beta. In addition, several new approaches to the use of different interleukins in the treatment of IBD have been described in recent years.
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Affiliation(s)
- David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland;
| | - Agnieszka Przygórzewska
- English Division Science Club, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland; (A.P.); (P.W.)
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland;
| | - Paweł Woźnicki
- English Division Science Club, Medical College of The Rzeszów University, 35-310 Rzeszów, Poland; (A.P.); (P.W.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland;
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Ignacio A, Cipelli M, Takiishi T, Favero Aguiar C, Fernandes Terra F, Ghirotto B, Martins Silva E, Castoldi A, Magalhães YT, Antonio T, Nunes Padovani B, Ioshie Hiyane M, Andrade-Oliveira V, Forti FL, Olsen Saraiva Camara N. Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis. J Leukoc Biol 2024; 116:779-792. [PMID: 38652699 DOI: 10.1093/jleuko/qiae084] [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: 05/24/2023] [Revised: 01/30/2024] [Accepted: 03/05/2024] [Indexed: 04/25/2024] Open
Abstract
The mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in CD11c+ myeloid cells (referred to here as CD11cRicΔ/Δ), we investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon dextran sulfate sodium-induced colitis, the lack of mTORC2 signaling CD11c+ cells diminishes the colitis score and abrogates DC migration to the mesenteric lymph nodes, thereby diminishing the infiltration of T helper 17 cells in the lamina propria and subsequent inflammation. These findings corroborate with the abrogation of cytoskeleton organization and the decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis patients revealed increased gene expression of proinflammatory cytokines, which coincided with augmented expression of the mTOR pathway, a positive correlation between the DC marker ITGAX and interleukin-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses, and this way, ameliorates the progression and severity of intestinal inflammatory diseases.
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Affiliation(s)
- Aline Ignacio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Marcella Cipelli
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Tatiane Takiishi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Cristhiane Favero Aguiar
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Fernanda Fernandes Terra
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Bruno Ghirotto
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Eloisa Martins Silva
- Center for Natural and Human Sciences, Federal University of ABC. Alameda da Universidade (UFABC) 09606045, São Bernardo do Campo, SP, Brazil
| | - Angela Castoldi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Yuli Thamires Magalhães
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo. Av. Prof. Lineu Prestes, 748 05508900, São Paulo, Brazil
| | - Tiago Antonio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Barbara Nunes Padovani
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Meire Ioshie Hiyane
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Vinicius Andrade-Oliveira
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Fabio Luis Forti
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo. Av. Prof. Lineu Prestes, 748 05508900, São Paulo, Brazil
| | - Niels Olsen Saraiva Camara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
- Laboratory of Renal Physiology, Department of Medicine, Federal University of São Paulo (UNIFESP). Rua Botucatu 740, 04023-062, São Paulo, Brazil
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4
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Paula Sanchez Zanotti M, Cataldi de Alcântara C, Junko Inoue C, Piantoni Gonçalves B, Rabello Espinosa B, Luiz Cândido de Souza Cassela P, Lerner Trigo G, Mendes Ahrens T, Alysson Batisti Lozovoy M, Eduardo Coral de Oliveira C, Maria Vissoci Reiche E, Name Colado Simão A. Involvement of IL17A and IL17RA variants in interleukin-17A levels and disease activity in ulcerative colitis. Cytokine 2024; 182:156716. [PMID: 39111114 DOI: 10.1016/j.cyto.2024.156716] [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: 04/03/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/25/2024]
Abstract
Ulcerative colitis (UC) is characterized by chronic inflammation of the large intestine with involvement of Th17 cells and interleukin (IL)-17A. The role of IL17A and IL17A receptor (IL17RA) variants in pathophysiology of UC still remains inconclusive. The aim was to evaluate the association between IL17A and IL17RA variants with susceptibility, IL-17A plasma levels, and endoscopic activity in UC. The study included 104 patients with UC and 213 controls. Patients were divided according to endoscopic activity (remission/mild and moderate/severe). The IL17A rs3819024 A>G and rs3819025 G>A, and IL17RA rs2241043 C>T, rs2241049 A>G, and rs6518661 G>A variants were genotyped using real time polymerase chain reaction. IL-17A plasma levels were determined using immunofluorimetric assay. Neither IL17A nor IL17RA variants were associated with UC susceptibility. The IL17A rs3819024 AG genotype was associated to high levels of IL-17 only in patients. Patients with the G allele of IL17RA rs2241049 showed 2.944 more chance of developing moderate/severe disease. The haplotype analysis showed that IL17RA rs2241049 and rs6518661 was not associated with UC susceptibility and haplotypes constituted with G allele of these variants were not associated with disease severity (p = 0.09). In conclusion, the IL17A rs3819024 AG genotype was associated with elevated IL-17A plasma levels in patients with UC but not in controls and the IL17RA rs2241049 AG+GG genotypes were associated to severity of UC. These results suggest a possible hidden interaction between the IL17A rs3819024 variant and other genetic, environmental, and epigenetic factors in the IL-17A expression that is present only in patients with UC.
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Affiliation(s)
- Mariana Paula Sanchez Zanotti
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil; Department of Gastroenterology, University of Londrina, Londrina, PR, Brazil
| | | | - Cláudia Junko Inoue
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil; Department of Gastroenterology, University of Londrina, Londrina, PR, Brazil
| | - Beatriz Piantoni Gonçalves
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil; Department of Gastroenterology, University of Londrina, Londrina, PR, Brazil
| | | | | | - Guilherme Lerner Trigo
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil
| | - Tainah Mendes Ahrens
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil
| | - Marcell Alysson Batisti Lozovoy
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil; Department of Pathology, Clinical Analysis and Toxicology, Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil
| | - Carlos Eduardo Coral de Oliveira
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, Londrina State University, Londrina, Paraná, Brazil; Pontifical Catholic University of Paraná, School of Medicine, Campus Londrina, Londrina, Paraná, Brazil.
| | - Edna Maria Vissoci Reiche
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, Londrina State University, Londrina, Paraná, Brazil; Pontifical Catholic University of Paraná, School of Medicine, Campus Londrina, Londrina, Paraná, Brazil.
| | - Andréa Name Colado Simão
- Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil; Department of Pathology, Clinical Analysis and Toxicology, Laboratory of Research in Applied Immunology, University of Londrina, Londrina, PR, Brazil.
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Yin Y, Wang R, Li Y, Qin W, Pan L, Yan C, Hu Y, Wang G, Ai L, Mei Q, Li L. Protection against DSS-induced colitis in mice through FcεRIα deficiency: the role of altered Lactobacillus. NPJ Biofilms Microbiomes 2024; 10:84. [PMID: 39266529 PMCID: PMC11393424 DOI: 10.1038/s41522-024-00563-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/27/2024] [Indexed: 09/14/2024] Open
Abstract
The role of mast cells (MCs) in ulcerative colitis (UC) development is controversial. FcεRI, the IgE high-affinity receptor, is known to activate MCs. However, its role in UC remains unclear. In our study, Anti-FcεRI showed highly diagnostic value for UC. FcεRIα knockout in mice ameliorated DSS-induced colitis in a gut microbiota-dependent manner. Increased Lactobacillus abundance in FcεRIα deficient mice showed strongly correlation with the remission of colitis. RNA sequencing indicated activation of the NLRP6 inflammasome pathway in FcεRIα knockout mice. Additionally, Lactobacillus plantarum supplementation protected against inflammatory injury and goblet cell loss, with activation of the NLRP6 inflammasome during colitis. Notably, this effect was absent when the strain is unable to produce lactic acid. In summary, colitis was mitigated in FcεRIα deficient mice, which may be attributed to the increased abundance of Lactobacillus. These findings contribute to a better understanding of the relationship between allergic reactions, microbiota, and colitis.
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Affiliation(s)
- Yue Yin
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruilong Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yanning Li
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenfei Qin
- School of Health Science and Engineering, Shanghai Engineering Research Center of Food Microbiology, University of Shanghai for Science and Technology, Shanghai, China
| | - Letian Pan
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Chenyuan Yan
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yusen Hu
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Guangqiang Wang
- School of Health Science and Engineering, Shanghai Engineering Research Center of Food Microbiology, University of Shanghai for Science and Technology, Shanghai, China
| | - Lianzhong Ai
- School of Health Science and Engineering, Shanghai Engineering Research Center of Food Microbiology, University of Shanghai for Science and Technology, Shanghai, China.
| | - Qixiang Mei
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China.
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Li Li
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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6
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Sisnett DJ, Zutautas KB, Miller JE, Lingegowda H, Ahn SH, McCallion A, Bougie O, Lessey BA, Tayade C. The Dysregulated IL-23/TH17 Axis in Endometriosis Pathophysiology. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1428-1441. [PMID: 38466035 DOI: 10.4049/jimmunol.2400018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024]
Abstract
Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor in the development and differentiation of TH17 cells, driving TH17 cells toward a pathogenic profile. In a variety of inflammatory and autoimmune disorders, TH17 cells secrete proinflammatory cytokines, including IL-17, contributing to disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. In this article, we address whether IL-23-driven TH17 cells contribute to cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. The results indicated dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared with controls. In vitro studies using primary human TH cells determined that rIL-23 mixture treatment increased pathogenic TH17 cell frequency. Similarly, rIL-23 treatment of cell lines (12Z cells, EECCs, HUVECs, and hESCs) representative of the endometriotic lesion microenvironment increased cytokines and growth factors, which play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, rIL-23 treatment altered numbers of myeloid and T cell subsets in peritoneal fluid and increased giant cells within the lesion. Lesions from rIL-23-treated mice did not reveal significant alterations in proliferation/vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on endometriosis pathophysiology.
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Affiliation(s)
- Danielle J Sisnett
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Katherine B Zutautas
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Jessica E Miller
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | | | - Soo Hyun Ahn
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Alison McCallion
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Olga Bougie
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
- Department of Obstetrics and Gynaecology, Kingston Health Sciences Centre, Kingston, ON, Canada
| | - Bruce A Lessey
- School of Medicine, Wake Forest University, Winston-Salem, NC
| | - Chandrakant Tayade
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
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7
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Ohara D, Takeuchi Y, Watanabe H, Lee Y, Mukoyama H, Ohteki T, Kondoh G, Hirota K. Notch2 with retinoic acid license IL-23 expression by intestinal EpCAM+ DCIR2+ cDC2s in mice. J Exp Med 2024; 221:e20230923. [PMID: 38180443 PMCID: PMC10770806 DOI: 10.1084/jem.20230923] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 11/06/2023] [Accepted: 12/07/2023] [Indexed: 01/06/2024] Open
Abstract
Despite the importance of IL-23 in mucosal host defense and disease pathogenesis, the mechanisms regulating the development of IL-23-producing mononuclear phagocytes remain poorly understood. Here, we employed an Il23aVenus reporter strain to investigate the developmental identity and functional regulation of IL-23-producing cells. We showed that flagellin stimulation or Citrobacter rodentium infection led to robust induction of IL-23-producing EpCAM+ DCIR2+ CD103- cDC2s, termed cDCIL23, which was confined to gut-associated lymphoid tissues, including the mesenteric lymph nodes, cryptopatches, and isolated lymphoid follicles. Furthermore, we demonstrated that Notch2 signaling was crucial for the development of EpCAM+ DCIR2+ cDC2s, and the combination of Notch2 signaling with retinoic acid signaling controlled their terminal differentiation into cDCIL23, supporting a two-step model for the development of gut cDCIL23. Our findings provide fundamental insights into the developmental pathways and cellular dynamics of IL-23-producing cDC2s at steady state and during pathogen infection.
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Affiliation(s)
- Daiya Ohara
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hitomi Watanabe
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yoonha Lee
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hiroki Mukoyama
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Toshiaki Ohteki
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Gen Kondoh
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Bai X, Zhang F, Zhou C, Yan J, Liang H, Zhu R, Gong M, Song H, Niu J, Miao Y. Identification of cuproptosis-related molecular classification and characteristic genes in ulcerative colitis. Heliyon 2024; 10:e24875. [PMID: 38312708 PMCID: PMC10835364 DOI: 10.1016/j.heliyon.2024.e24875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 02/06/2024] Open
Abstract
Ulcerative colitis (UC) is a refractory inflammatory disease with imbalances in intestinal mucosal homeostasis. Cuproptosis serves as newly identified programmed cell death (PCD) form involved in UC. In the study, UC-related datasets were extracted from the Gene Expression Omnibus (GEO) database. A comparison of UC patients and healthy controls identified 11 differentially expressed cuproptosis-related genes (DE-CRGs), where FDX1, LIAS, and DLAT were differentially expressed in UC groups from the mouse models and clinical samples, with their expression correlating with disease severity. By comprehending weighted gene co-expression network analysis (WGCNA) and differential expression analysis, the key genes common to the module genes relevant to different cuproptosis-related clusters and differentially expressed genes (DEGs) both in different clusters and patients with and without UC were identified using several bioinformatic analysis. Furthermore, the mRNA levels of four characteristic genes with diagnostic potential demonstrated significant decrease in both mouse models and clinical UC samples. Our discoveries offer a theoretical foundation for cuproptosis effect in UC.
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Affiliation(s)
- Xinyu Bai
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Fengrui Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Chan Zhou
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Jingxian Yan
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Hao Liang
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Rui Zhu
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Min Gong
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Huixian Song
- Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Junkun Niu
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, China
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9
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Hsu CY, Faisal Mutee A, Porras S, Pineda I, Ahmed Mustafa M, J Saadh M, Adil M, H A Z. Amphiregulin in infectious diseases: Role, mechanism, and potential therapeutic targets. Microb Pathog 2024; 186:106463. [PMID: 38036111 DOI: 10.1016/j.micpath.2023.106463] [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: 10/07/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
Amphiregulin (AREG) serves as a ligand for the epidermal growth factor receptor (EGFR) and is involved in vital biological functions, including inflammatory responses, tissue regeneration, and immune system function. Upon interaction with the EGFR, AREG initiates a series of signaling cascades necessary for several physiological activities, such as metabolism, cell cycle regulation, and cellular proliferation. Recent findings have provided evidence for the substantial role of AREG in maintaining the equilibrium of homeostasis in damaged tissues and preserving epithelial cell structure in the context of viral infections affecting the lungs. The development of resistance to influenza virus infection depends on the presence of type 1 cytokine responses. Following the eradication of the pathogen, the lungs are subsequently colonized by several cell types that are linked with type 2 immune responses. These cells contribute to the process of repairing and resolving the tissue injury and inflammation caused by infections. Following influenza infection, the activation of AREG promotes the regeneration of bronchial epithelial cells, enhancing the tissue's structural integrity and increasing the survival rate of infected mice. In the same manner, mice afflicted with influenza experience rapid mortality due to a subsequent bacterial infection in the pulmonary region when both bacterial and viral infections manifest concurrently inside the same host. The involvement of AREG in bacterial infections has been demonstrated. The gene AREG experiences increased transcriptional activity inside host cells in response to bacterial infections caused by pathogens such as Escherichia coli and Neisseria gonorrhea. In addition, AREG has been extensively studied as a mitogenic stimulus in epithelial cell layers. Consequently, it is regarded as a prospective contender that might potentially contribute to the observed epithelial cell reactions in helminth infection. Consistent with this finding, mice that lack the AREG gene exhibit a delay in the eradication of the intestinal parasite Trichuris muris. The observed delay is associated with a reduction in the proliferation rate of colonic epithelial cells compared to the infected animals in the control group. The aforementioned findings indicate that AREG plays a pivotal role in facilitating the activation of defensive mechanisms inside the epithelial cells of the intestinal tissue. The precise cellular sources of AREG in this specific context have not yet been determined. However, it is evident that the increased proliferation of the epithelial cell layer in infected mice is reliant on CD4+ T cells. The significance of this finding lies in its demonstration of the crucial role played by the interaction between immunological and epithelial cells in regulating the AREG-EGFR pathway. Additional research is necessary to delve into the cellular origins and signaling mechanisms that govern the synthesis of AREG and its tissue-protective properties, independent of infection.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan
| | | | - Sandra Porras
- Facultad de Mecánica, Escuela Superior Politécnica de Chimborazo (ESPOCH), Panamericana Sur km 1 1/2, Riobamba, 060155, Ecuador
| | - Indira Pineda
- Facultad de Salud Pública, Escuela Superior Politécnica de Chimborazo (ESPOCH), Panamericana Sur km 1 1/2, Riobamba, 060155, Ecuador
| | - Mohammed Ahmed Mustafa
- Department of Medical Laboratory Technology, Imam Jaafar AL-Sadiq University, Iraq; Department of Pathological Analyzes, College of Applied Sciences, University of Samarra, Iraq.
| | - Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan; Applied Science Research Center, Applied Science Private University, Amman, Jordan
| | | | - Zainab H A
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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10
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Liu B, Qian Y, Li Y, Shen X, Ye D, Mao Y, Sun X. Circulating levels of cytokines and risk of inflammatory bowel disease: evidence from genetic data. Front Immunol 2023; 14:1310086. [PMID: 38149258 PMCID: PMC10750389 DOI: 10.3389/fimmu.2023.1310086] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/27/2023] [Indexed: 12/28/2023] Open
Abstract
Background Prior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research. Objective We aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach. Materials and methods We selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn's disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation. Results Genetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn's disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines. Conclusion Our study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.
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Affiliation(s)
- Bin Liu
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Yu Qian
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Yanan Li
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Xiangting Shen
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Ding Ye
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Yingying Mao
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Xiaohui Sun
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
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11
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Khilwani R, Singh S. Systems Biology and Cytokines Potential Role in Lung Cancer Immunotherapy Targeting Autophagic Axis. Biomedicines 2023; 11:2706. [PMID: 37893079 PMCID: PMC10604646 DOI: 10.3390/biomedicines11102706] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/11/2023] [Accepted: 09/11/2023] [Indexed: 10/29/2023] Open
Abstract
Lung cancer accounts for the highest number of deaths among men and women worldwide. Although extensive therapies, either alone or in conjunction with some specific drugs, continue to be the principal regimen for evolving lung cancer, significant improvements are still needed to understand the inherent biology behind progressive inflammation and its detection. Unfortunately, despite every advancement in its treatment, lung cancer patients display different growth mechanisms and continue to die at significant rates. Autophagy, which is a physiological defense mechanism, serves to meet the energy demands of nutrient-deprived cancer cells and sustain the tumor cells under stressed conditions. In contrast, autophagy is believed to play a dual role during different stages of tumorigenesis. During early stages, it acts as a tumor suppressor, degrading oncogenic proteins; however, during later stages, autophagy supports tumor cell survival by minimizing stress in the tumor microenvironment. The pivotal role of the IL6-IL17-IL23 signaling axis has been observed to trigger autophagic events in lung cancer patients. Since the obvious roles of autophagy are a result of different immune signaling cascades, systems biology can be an effective tool to understand these interconnections and enhance cancer treatment and immunotherapy. In this review, we focus on how systems biology can be exploited to target autophagic processes that resolve inflammatory responses and contribute to better treatment in carcinogenesis.
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Affiliation(s)
| | - Shailza Singh
- Systems Medicine Laboratory, National Centre for Cell Science, SPPU Campus, Ganeshkhind Road, Pune 411007, India;
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12
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Korta A, Kula J, Gomułka K. The Role of IL-23 in the Pathogenesis and Therapy of Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:10172. [PMID: 37373318 DOI: 10.3390/ijms241210172] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Interleukin-23 (IL-23) is a proinflammatory cytokine produced mainly by macrophages and antigen-presenting cells (APCs) after antigenic stimulation. IL-23 plays a significant role as a mediator of tissue damage. Indeed, the irregularities in IL-23 and its receptor signaling have been implicated in inflammatory bowel disease. IL-23 interacts with both the innate and adaptive immune systems, and IL-23/Th17 appears to be involved in the development of chronic intestinal inflammation. The IL-23/Th17 axis may be a critical driver of this chronic inflammation. This review summarizes the main aspects of IL-23's biological function, cytokines that control cytokine production, effectors of the IL-23 response, and the molecular mechanisms associated with IBD pathogenesis. Although IL-23 modulates and impacts the development, course, and recurrence of the inflammatory response, the etiology and pathophysiology of IBD are not completely understood, but mechanism research shows huge potential for clinical applications as therapeutic targets in IBD treatment.
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Affiliation(s)
- Aleksandra Korta
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Julia Kula
- Student Scientific Group of Adult Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
| | - Krzysztof Gomułka
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, 50-369 Wroclaw, Poland
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13
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Li JH, Hepworth MR, O'Sullivan TE. Regulation of systemic metabolism by tissue-resident immune cell circuits. Immunity 2023; 56:1168-1186. [PMID: 37315533 PMCID: PMC10321269 DOI: 10.1016/j.immuni.2023.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/11/2023] [Accepted: 05/02/2023] [Indexed: 06/16/2023]
Abstract
Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
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Affiliation(s)
- Joey H Li
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA; Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Matthew R Hepworth
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA.
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14
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Apolit C, Campos N, Vautrin A, Begon-Pescia C, Lapasset L, Scherrer D, Gineste P, Ehrlich H, Garcel A, Santo J, Tazi J. ABX464 (Obefazimod) Upregulates miR-124 to Reduce Proinflammatory Markers in Inflammatory Bowel Diseases. Clin Transl Gastroenterol 2023; 14:e00560. [PMID: 36573890 PMCID: PMC10132720 DOI: 10.14309/ctg.0000000000000560] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 11/30/2022] [Indexed: 12/29/2022] Open
Abstract
Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively upregulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 affects the immune system in vitro , in the murine model of inflammatory bowel disease, and in patients with UC. In vitro , ABX464 treatment upregulated miR-124 and led to decreases in proinflammatory cytokines including interleukin (IL) 17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of patients with UC, and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By upregulating miR-124, ABX464 acts as "a physiological brake" of inflammation, which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in patients with UC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Jamal Tazi
- Abivax, Montpellier, France
- Abivax, Paris, France
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15
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Shalaby M, Abdеlaziz RR, Ghoneim HA, Suddеk GM. Imatinib mitigates experimentally-induced ulcerative colitis: Possible contribution of NF-kB/JAK2/STAT3/COX2 signaling pathway. Life Sci 2023; 321:121596. [PMID: 36940909 DOI: 10.1016/j.lfs.2023.121596] [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: 02/01/2023] [Revised: 03/06/2023] [Accepted: 03/15/2023] [Indexed: 03/22/2023]
Abstract
RATIONALE Ulcerative colitis (UC) is a chronic immune-mediated disease characterized by recurrent inflammation, damage, and alteration of the large intestine's mucosal and submucosal surfaces. The purpose of this research was to evaluate the impact of tyrosine kinase inhibitor (imatinib) on experimentally induced UC in rats via acetic acid (AA). METHODS Male rats were randomly assigned to four groups: control, AA, AA + imatinib (10 mg/kg), and AA + imatinib (20 mg/kg). Imatinib (10 and 20 mg/kg/day) was orally supplied by oral syringe for one week before induction of UC. On the eighth day, Rats received enemas containing a 4 % solution of acetic acid to induce colitis. One day after inducing colitis, rats were euthanized and their colons were subjected to morphological, biochemical, histological, and immunohistochemical analysis. RESULTS Imatinib pretreatment significantly decreased macroscopic and histological damage scores, decreased disease activity index as well as colon mass index. In addition, imatinib successfully lowered the levels of malondialdehyde (MDA) in colonic tissues and enhanced superoxide dismutase activity (SOD) and glutathione content (GSH). Imatinib also reduced colonic levels of inflammatory interleukins (IL-23, IL-17, IL-6), JAK2 and STAT3. Furthermore, imatinib suppressed nuclear transcription factor kappa B (NF-kB/p65) level, and COX2 expression in colonic tissues. SIGNIFICANCE Imatinib may be a viable therapy option for UC as it halts the interaction network of NF-kB/JAK2/STAT3/COX2 signaling pathway.
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Affiliation(s)
- Mohamed Shalaby
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt
| | - Rania R Abdеlaziz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
| | - Hamdy A Ghoneim
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt
| | - Ghada M Suddеk
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt
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16
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Gao XY, Jin Y, Zhao J, Zhang YL, Wang HW, Zhou BH. Th17-Related Cytokines Involved in Fluoride-Induced Cecal and Rectal Barrier Damage of Ovariectomized Rats. Biol Trace Elem Res 2022:10.1007/s12011-022-03519-6. [PMID: 36538210 DOI: 10.1007/s12011-022-03519-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
To investigate fluoride (F)-induced intestine barrier damage and the role of estrogen deficiency in this progress, a rat model of estrogen deficiency was established through bilateral surgical removal of ovaries. The F exposure model was then continued by adding sodium fluoride (0, 25, 50, and 100 mg/L, calculated on a fluorine ion basis) to drinking water for 90 days. Afterward, intestinal mucosal structure, barrier function, and inflammatory cytokines were evaluated. The results showed that excessive F decreased the developmental parameters (crypt depth) of the cecum and rectum and inhibited the proliferation capacity of the intestinal epithelia, which are more obvious in the state of estrogen deficiency. The distribution of goblet cells and glycoproteins in the intestinal mucosa decreased with the increase in F concentration, and estrogen deficiency led to a further decline, especially in the rectum. Using the immunofluorescence method, the study showed that excessive F caused interleukin-17A (IL-17A) significantly decrease in the cecum and increase in the rectum. Meanwhile, F treatment remarkably upregulated the expression of intestinal IL-1β, IL-23, and IL-22, while the level of IL-6 was downregulated. In addition, estrogen deficiency increased IL-1β, IL-6, IL-23, and IL-22, but decreased IL-17A expression in the cecum and rectum. Collectively, F exposure damaged intestinal morphological structure, inhibited epithelial cell proliferation and mucus barrier function, and resulted in the disturbance of T helper (Th) 17 cell-related cytokines expression. Estrogen deficiency may further aggravate F-induced damage to the cecum and rectum.
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Affiliation(s)
- Xiao-Ying Gao
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Ye Jin
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Jing Zhao
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Yu-Ling Zhang
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Hong-Wei Wang
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Bian-Hua Zhou
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China.
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17
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Al-Hakeim HK, Al-Musawi AF, Al-Mulla A, Al-Dujaili AH, Debnath M, Maes M. The interleukin-6/interleukin-23/T helper 17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: A precision nomothetic psychiatry analysis. PLoS One 2022; 17:e0275839. [PMID: 36256663 PMCID: PMC9578624 DOI: 10.1371/journal.pone.0275839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 09/24/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Schizophrenia and especially deficit schizophrenia (DSCZ) are characterized by increased activity of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There is no data on whether the interleukin (IL)-6/IL-23/T helper 17 (IL-6/IL-23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. METHODS This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL-6/IL-23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and the schizophrenia phenome. RESULTS Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL-6/IL-23/Th17-axis score, as assessed by an LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL-6/IL-23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL-6/IL-23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). CONCLUSION The pathogenic IL-6/IL-23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia, especially that of DSCZ, due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.
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Affiliation(s)
| | - Ali Fattah Al-Musawi
- Department of Clinical Pharmacy and Laboratory Sciences, College of Pharmacy, University of Al-Kafeel, Kufa, Iraq
| | - Abbas Al-Mulla
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
- IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia
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18
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Jha A, Ahad A, Mishra GP, Sen K, Smita S, Minz AP, Biswas VK, Tripathy A, Senapati S, Gupta B, Acha-Orbea H, Raghav SK. SMRT and NCoR1 fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling. Front Immunol 2022; 13:910705. [PMID: 36238311 PMCID: PMC9552960 DOI: 10.3389/fimmu.2022.910705] [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: 04/01/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4+ and CD8+ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 (Smrt) depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8+ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.
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Affiliation(s)
- Atimukta Jha
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Manipal Academy of Higher Education, Manipal, KA, India
| | - Abdul Ahad
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Manipal Academy of Higher Education, Manipal, KA, India
| | - Gyan Prakash Mishra
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Kaushik Sen
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, Haryana, India
| | - Shuchi Smita
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Manipal Academy of Higher Education, Manipal, KA, India
| | - Aliva Prity Minz
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
| | - Viplov Kumar Biswas
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Archana Tripathy
- Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Shantibhushan Senapati
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Manipal Academy of Higher Education, Manipal, KA, India
| | - Bhawna Gupta
- Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Hans Acha-Orbea
- Department of Biochemistry Center of Immunity and Infection Lausanne (CIIL), University of Lausanne (UNIL), Epalinges, Switzerland
| | - Sunil Kumar Raghav
- Immuno-genomics & Systems Biology laboratory, Institute of Life Sciences (ILS), Bhubaneswar, OR, India
- Manipal Academy of Higher Education, Manipal, KA, India
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19
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Ghilas S, O’Keefe R, Mielke LA, Raghu D, Buchert M, Ernst M. Crosstalk between epithelium, myeloid and innate lymphoid cells during gut homeostasis and disease. Front Immunol 2022; 13:944982. [PMID: 36189323 PMCID: PMC9524271 DOI: 10.3389/fimmu.2022.944982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/29/2022] [Indexed: 12/05/2022] Open
Abstract
The gut epithelium not only provides a physical barrier to separate a noxious outside from a sterile inside but also allows for highly regulated interactions between bacteria and their products, and components of the immune system. Homeostatic maintenance of an intact epithelial barrier is paramount to health, requiring an intricately regulated and highly adaptive response of various cells of the immune system. Prolonged homeostatic imbalance can result in chronic inflammation, tumorigenesis and inefficient antitumor immune control. Here we provide an update on the role of innate lymphoid cells, macrophages and dendritic cells, which collectively play a critical role in epithelial barrier maintenance and provide an important linkage between the classical innate and adaptive arm of the immune system. These interactions modify the capacity of the gut epithelium to undergo continuous renewal, safeguard against tumor formation and provide feedback to the gut microbiome, which acts as a seminal contributor to cellular homeostasis of the gut.
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Affiliation(s)
- Sonia Ghilas
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Ryan O’Keefe
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Lisa Anna Mielke
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Dinesh Raghu
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Michael Buchert
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
- *Correspondence: Michael Buchert, ; Matthias Ernst,
| | - Matthias Ernst
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
- *Correspondence: Michael Buchert, ; Matthias Ernst,
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20
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Carnac T. Schizophrenia Hypothesis: Autonomic Nervous System Dysregulation of Fetal and Adult Immune Tolerance. Front Syst Neurosci 2022; 16:844383. [PMID: 35844244 PMCID: PMC9283579 DOI: 10.3389/fnsys.2022.844383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
The autonomic nervous system can control immune cell activation via both sympathetic adrenergic and parasympathetic cholinergic nerve release of norepinephrine and acetylcholine. The hypothesis put forward in this paper suggests that autonomic nervous system dysfunction leads to dysregulation of immune tolerance mechanisms in brain-resident and peripheral immune cells leading to excessive production of pro-inflammatory cytokines such as Tumor Necrosis Factor alpha (TNF-α). Inactivation of Glycogen Synthase Kinase-3β (GSK3β) is a process that takes place in macrophages and microglia when a toll-like receptor 4 (TLR4) ligand binds to the TLR4 receptor. When Damage-Associated Molecular Patterns (DAMPS) and Pathogen-Associated Molecular Patterns (PAMPS) bind to TLR4s, the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway should be activated, leading to inactivation of GSK3β. This switches the macrophage from producing pro-inflammatory cytokines to anti-inflammatory cytokines. Acetylcholine activation of the α7 subunit of the nicotinic acetylcholine receptor (α7 nAChR) on the cell surface of immune cells leads to PI3K/Akt pathway activation and can control immune cell polarization. Dysregulation of this pathway due to dysfunction of the prenatal autonomic nervous system could lead to impaired fetal immune tolerance mechanisms and a greater vulnerability to Maternal Immune Activation (MIA) resulting in neurodevelopmental abnormalities. It could also lead to the adult schizophrenia patient’s immune system being more vulnerable to chronic stress-induced DAMP release. If a schizophrenia patient experiences chronic stress, an increased production of pro-inflammatory cytokines such as TNF-α could cause significant damage. TNF-α could increase the permeability of the intestinal and blood brain barrier, resulting in lipopolysaccharide (LPS) and TNF-α translocation to the brain and consequent increases in glutamate release. MIA has been found to reduce Glutamic Acid Decarboxylase mRNA expression, resulting in reduced Gamma-aminobutyric acid (GABA) synthesis, which combined with an increase of glutamate release could result in an imbalance of glutamate and GABA neurotransmitters. Schizophrenia could be a “two-hit” illness comprised of a genetic “hit” of autonomic nervous system dysfunction and an environmental hit of MIA. This combination of factors could lead to neurotransmitter imbalance and the development of psychotic symptoms.
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Țiburcă L, Bembea M, Zaha DC, Jurca AD, Vesa CM, Rațiu IA, Jurca CM. The Treatment with Interleukin 17 Inhibitors and Immune-Mediated Inflammatory Diseases. Curr Issues Mol Biol 2022; 44:1851-1866. [PMID: 35678656 PMCID: PMC9164043 DOI: 10.3390/cimb44050127] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/23/2022] [Accepted: 04/24/2022] [Indexed: 12/29/2022] Open
Abstract
IL-17 inhibitors (IL-17i) are medicines used to treat dermatological and rheumatic diseases They belong to a class of medicines called biological disease-modifying anti-rheumatic drugs (bDMARDs). This class of drugs has had a major impact on the therapy of autoimmune diseases, being much safer and more effective than treatment with small molecules. At the same time, they have highly beneficial effects on skin and joint changes, and their efficacy has been extensively monitored and demonstrated in numerous clinical trials. More and more such drugs are still being discovered today to ensure the best possible treatment of these patients, but more frequently and relatively constantly three agents are used. Two of them (Secukinumab and Ixekizumab) inhibit IL-17A directly, and the third, Brodamulab, inhibits the IL-17A receptor. Although they are extremely effective in the treatment of these diseases, sometimes their administration has been associated with paradoxical effects, i.e., there is an exacerbation of the inflammatory process. Tough, clinical trials of IL-17i have described cases of exacerbation or even onset of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, after administration of these drugs in patients previously diagnosed with psoriasis (PS), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). The pathophysiological mechanism of action is not well understood at present. One explanation would be that this hyperreactive inflammatory process would be triggered by Interferon 1 derived from dendritic plasma cells. Even though there are many reports in the recent literature about the role of IL17i in the onset of IBD, conclusions of studies do not converge. Some of them show an increased incidence of IBD in patients treated with IL17i, while some others affirm their safety of them. In the near future we will surely have more data emerging from ongoing meta-analyses regarding safety of use IL17i in patients who are at risk of developing IBD. Clinical and paraclinical evaluation (inflammatory intestinal markers) are carefully advised before recommending treatment with IL-17i and after initiation of treatment, and prospective surveillance by clinical and biomarkers of patients treated with IL-17i is absolutely essential to capture the onset of IBD.
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Affiliation(s)
- Laura Țiburcă
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
- “Dr. Gavril Curteanu” Clinical Hospital Regional Center of Medical Genetics Bihor, 410469 Oradea, Romania;
| | - Marius Bembea
- “Dr. Gavril Curteanu” Clinical Hospital Regional Center of Medical Genetics Bihor, 410469 Oradea, Romania;
| | - Dana Carmen Zaha
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Alexandru Daniel Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Cosmin Mihai Vesa
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Ioana Adela Rațiu
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
| | - Claudia Maria Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, 1 December 10 Square, 410087 Oradea, Romania; (L.Ț.); (C.M.V.); (I.A.R.); (C.M.J.)
- “Dr. Gavril Curteanu” Clinical Hospital Regional Center of Medical Genetics Bihor, 410469 Oradea, Romania;
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22
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Czaja AJ. Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis. Dig Dis Sci 2022; 67:1163-1186. [PMID: 33835375 DOI: 10.1007/s10620-021-06968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8+ T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4+ and CD8+ T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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23
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Feng Y, Chen Z, Tu SQ, Wei JM, Hou YL, Kuang ZL, Kang XN, Ai H. Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chronic Inflammatory Diseases. Front Immunol 2022; 13:862415. [PMID: 35371044 PMCID: PMC8968732 DOI: 10.3389/fimmu.2022.862415] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 02/28/2022] [Indexed: 01/02/2023] Open
Abstract
Periodontitis is a chronic inflammatory and destructive disease caused by periodontal microbial infection and mediated by host immune response. As the main cause of loosening and loss of teeth in adults, it is considered to be one of the most common and serious oral diseases in the world. The co-existence of periodontitis and systemic chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, diabetes and so on is very common. It has been found that interleukin-17A (IL-17A) secreted by various innate and adaptive immune cells can activate a series of inflammatory cascade reactions, which mediates the occurrence and development of periodontitis and related systemic chronic inflammatory diseases. In this work, we review the role of IL-17A in the pathomechanisms of periodontitis and related systemic chronic inflammatory diseases, and briefly discuss the therapeutic potential of cytokine targeted agents that modulate the IL-17A signaling. A deep understanding of the possible molecular mechanisms in the relationship between periodontitis and systemic diseases will help dentists and physicians update their clinical diagnosis and treatment ideas.
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24
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Huo J, Wu Z, Sun W, Wang Z, Wu J, Huang M, Wang B, Sun B. Protective Effects of Natural Polysaccharides on Intestinal Barrier Injury: A Review. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:711-735. [PMID: 35078319 DOI: 10.1021/acs.jafc.1c05966] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Owing to their minimal side effects and effective protection from oxidative stress, inflammation, and malignant growth, natural polysaccharides (NPs) are a potential adjuvant therapy for several diseases caused by intestinal barrier injury (IBI). More studies are accumulating on the protective effects of NPs with respect to IBI, but the underlying mechanisms remain unclear. Thus, this review aims to represent current studies that investigate the protective effects of NPs on IBI by directly maintaining intestinal epithelial barrier integrity (inhibiting oxidative stress, regulating inflammatory cytokine expression, and increasing tight junction protein expression) and indirectly regulating intestinal immunity and microbiota. Furthermore, the mechanisms underlying IBI development are briefly introduced, and the structure-activity relationships of polysaccharides with intestinal barrier protection effects are discussed. Potential developments and challenges associated with NPs exhibiting protective effects against IBI have also been highlighted to guide the application of NPs in the treatment of intestinal diseases caused by IBI.
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Affiliation(s)
- Jiaying Huo
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510640, People's Republic of China
| | - Ziyan Wu
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Weizheng Sun
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510640, People's Republic of China
| | - Zhenhua Wang
- Center for Mitochondria and Healthy Aging, College of Life Science, Yantai University, Yantai, Shandong 264005, People's Republic of China
| | - Jihong Wu
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Mingquan Huang
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Bowen Wang
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
| | - Baoguo Sun
- Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, People's Republic of China
- Beijing Laboratory of Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, People's Republic of China
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25
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Lu L, Liu YJ, Cheng PQ, Hu D, Xu HC, Ji G. Macrophages play a role in inflammatory transformation of colorectal cancer. World J Gastrointest Oncol 2021; 13:2013-2028. [PMID: 35070038 PMCID: PMC8713318 DOI: 10.4251/wjgo.v13.i12.2013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/21/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, and it is also a typical inflammatory cancer. The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation. Here, we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages. Furthermore, the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized. In addition, in the era of tumor immunotherapy, CRC currently has a limited response rate to immune checkpoint inhibitors, and we summarize potential therapeutic strategies for targeting tumor-associated macrophages.
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Affiliation(s)
- Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yu-Jing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Pei-Qiu Cheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Han-Chen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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26
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Thomas JP, Modos D, Korcsmaros T, Brooks-Warburton J. Network Biology Approaches to Achieve Precision Medicine in Inflammatory Bowel Disease. Front Genet 2021; 12:760501. [PMID: 34745229 PMCID: PMC8566351 DOI: 10.3389/fgene.2021.760501] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition arising due to complex interactions between multiple genetic and environmental factors. Despite recent advances, the pathogenesis of the condition is not fully understood and patients still experience suboptimal clinical outcomes. Over the past few years, investigators are increasingly capturing multi-omics data from patient cohorts to better characterise the disease. However, reaching clinically translatable endpoints from these complex multi-omics datasets is an arduous task. Network biology, a branch of systems biology that utilises mathematical graph theory to represent, integrate and analyse biological data through networks, will be key to addressing this challenge. In this narrative review, we provide an overview of various types of network biology approaches that have been utilised in IBD including protein-protein interaction networks, metabolic networks, gene regulatory networks and gene co-expression networks. We also include examples of multi-layered networks that have combined various network types to gain deeper insights into IBD pathogenesis. Finally, we discuss the need to incorporate other data sources including metabolomic, histopathological, and high-quality clinical meta-data. Together with more robust network data integration and analysis frameworks, such efforts have the potential to realise the key goal of precision medicine in IBD.
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Affiliation(s)
- John P Thomas
- Earlham Institute, Norwich, United Kingdom
- Quadram Institute Bioscience, Norwich, United Kingdom
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - Dezso Modos
- Earlham Institute, Norwich, United Kingdom
- Quadram Institute Bioscience, Norwich, United Kingdom
| | - Tamas Korcsmaros
- Earlham Institute, Norwich, United Kingdom
- Quadram Institute Bioscience, Norwich, United Kingdom
| | - Johanne Brooks-Warburton
- Department of Gastroenterology, Lister Hospital, Stevenage, United Kingdom
- Department of Clinical, Pharmaceutical and Biological Sciences, University of Hertfordshire, Hatfield, United Kingdom
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Hu Y, Gu J, Wang Y, Lin J, Yu H, Yang F, Wu S, Yin J, Lv H, Ji X, Wang S. Promotion Effect of EGCG on the Raised Expression of IL-23 through the Signaling of STAT3-BATF2-c-JUN/ATF2. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:7898-7909. [PMID: 34227806 DOI: 10.1021/acs.jafc.1c02433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Tea polyphenol of epigallocatechin-3-gallate (EGCG) has been verified to possess multiple biological activities. Interleukin-23 (IL-23) is a heterodimeric cytokine consisting of two subunits of IL-23p19 and IL-12p40, with the functionality in regulating the production of cytokines under physiological or pathological conditions. By serendipity, the raised expression of IL-23 was observed after treating cells with EGCG, whereas the detailed mechanism remains poorly understood. This study was proposed to investigate the signaling related to EGCG-induced IL-23. The raised expression of IL-23 was confirmed primarily by intraperitoneally injecting with different concentrations of EGCG (0, 20, 50, 80 mg/kg) into BALB/c mice, and the raised expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results from enzyme-linked immunosorbent assay (ELISA) revealed the increase of IL-23 in serum from 116.09 to 153.90 pg/mL after treating with EGCG. The same results were also observed in RAW264.7 and peritoneal macrophages after treating with EGCG (0, 1, 5, 10, 25 μM) with the increased tendency of IL-23 in cultural medium (7.98 to 25.38 pg/mL for RAW264.7; 3.64 to 260.93 pg/mL for peritoneal macrophages). After preliminary exploration of the signaling related to the increased IL-23, the classical signaling pathways and key transcription factors, such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) signaling pathways, and interferon regulatory factor 5 (IRF5), were demonstrated with no relevant contribution. A further study revealed the involvement of the key transcription factor of BATF2, which could antagonistically modulate the transcription and translation of IL-23. The signaling of STAT3-BATF2-c-JUN/ATF2-IL-23 has been further verified in RAW264.7 macrophages using the STAT3 inhibitor of AG490 and the activator of Colivelin TFA. The results indicated that EGCG inhibits the phosphorylation of STAT3 to facilitate the decreased level of BATF2, which contributed to the increased level of IL-23 by the enhancing heterodimerization of c-JUN and ATF2.
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Affiliation(s)
- Yaozhong Hu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jiaxin Gu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Yi Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jing Lin
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Huaning Yu
- Guangdong Midea Kitchen Appliances Manufacturing Co., Ltd, Guangdong 528000, China
| | - Feier Yang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Sihao Wu
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jia Yin
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Huan Lv
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Xuemeng Ji
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Shuo Wang
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
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Noviello D, Mager R, Roda G, Borroni RG, Fiorino G, Vetrano S. The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges. Front Immunol 2021; 12:611256. [PMID: 34079536 PMCID: PMC8165319 DOI: 10.3389/fimmu.2021.611256] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Colitis, Ulcerative/diagnosis
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Disease Management
- Disease Susceptibility
- Gastrointestinal Microbiome/drug effects
- Gastrointestinal Microbiome/immunology
- Humans
- Immunomodulation/drug effects
- Interleukin-17/metabolism
- Interleukin-23/metabolism
- Molecular Targeted Therapy
- Signal Transduction/drug effects
- Treatment Outcome
- Ustekinumab/pharmacology
- Ustekinumab/therapeutic use
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Affiliation(s)
- Daniele Noviello
- Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
| | - Riccardo Mager
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Giulia Roda
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Inflammatory Bowel Disease (IBD) Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Riccardo G. Borroni
- Inflammatory Bowel Disease (IBD) Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Dermatology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Gionata Fiorino
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Inflammatory Bowel Disease (IBD) Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Stefania Vetrano
- Inflammatory Bowel Disease (IBD) Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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29
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Huot N, Rascle P, Tchitchek N, Wimmer B, Passaes C, Contreras V, Desjardins D, Stahl-Hennig C, Le Grand R, Saez-Cirion A, Jacquelin B, Müller-Trutwin M. Role of NKG2a/c +CD8 + T cells in pathogenic versus non-pathogenic SIV infections. iScience 2021; 24:102314. [PMID: 33870131 PMCID: PMC8040270 DOI: 10.1016/j.isci.2021.102314] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 02/12/2021] [Accepted: 03/11/2021] [Indexed: 01/10/2023] Open
Abstract
Some viruses have established an equilibrium with their host. African green monkeys (AGM) display persistent high viral replication in the blood and intestine during Simian immunodeficiency virus (SIV) infection but resolve systemic inflammation after acute infection and lack intestinal immune or tissue damage during chronic infection. We show that NKG2a/c+CD8+ T cells increase in the blood and intestine of AGM in response to SIVagm infection in contrast to SIVmac infection in macaques, the latter modeling HIV infection. NKG2a/c+CD8+ T cells were not expanded in lymph nodes, and CXCR5+NKG2a/c+CD8+ T cell frequencies further decreased after SIV infection. Genome-wide transcriptome analysis of NKG2a/c+CD8+ T cells from AGM revealed the expression of NK cell receptors, and of molecules with cytotoxic effector, gut homing, and immunoregulatory and gut barrier function, including CD73. NKG2a/c+CD8+ T cells correlated negatively with IL-23 in the intestine during SIVmac infection. The data suggest a potential regulatory role of NKG2a/c+CD8+ T cells in intestinal inflammation during SIV/HIV infections.
Molecular determination of NKG2a/c+CD8+ T cells in two species of nonhuman primates Tissue distribution of NKG2a/c+CD8+ T cell is profoundly sculpted by SIV infections Intestinal NKG2a/c+CD8+ T cells correlated negatively with IL-23 in SIV infection NKG2a/c+CD8+ T cells might play a protective gut barrier function in HIV/SIV infection
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Affiliation(s)
- Nicolas Huot
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France
| | - Philippe Rascle
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Nicolas Tchitchek
- Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), Paris, France
| | - Benedikt Wimmer
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France
| | - Caroline Passaes
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France
| | - Vanessa Contreras
- CEA-Université Paris Sud-Inserm, U1184, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
| | - Delphine Desjardins
- CEA-Université Paris Sud-Inserm, U1184, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
| | - Christiane Stahl-Hennig
- Deutsches Primatenzentrum - Leibniz Institut für Primatenforschung, Unit of Infection Models, Göttingen, Germany
| | - Roger Le Grand
- CEA-Université Paris Sud-Inserm, U1184, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
| | - Asier Saez-Cirion
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France
| | - Beatrice Jacquelin
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France
| | - Michaela Müller-Trutwin
- Institut Pasteur, Unité HIV, Inflammation et Persistance, 28 rue du Dr Roux, Paris 75015, France
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Miao Z, Chen L, Feng H, Gu M, Yan J, Xu Y, Ye B. Baitouweng Decoction Ameliorates Ulcerative Colitis in Mice Partially Attributed to Regulating Th17/Treg Balance and Restoring Intestinal Epithelial Barrier. Front Pharmacol 2021; 11:531117. [PMID: 33597862 PMCID: PMC7883596 DOI: 10.3389/fphar.2020.531117] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic intestinal disease with unclear pathogenesis. With an increasing global prevalence over the past two decades, UC poses a serious threat to public health. Baitouweng decoction (BTW), a traditional Chinese medicine, has been shown to have good clinical efficacy for treating intestinal inflammation. Yet, the efficacy of BTW in UC and the underlying mechanism remain unclear. The current study aimed to determine whether BTW suppressed intestinal inflammation in mice and the potential mechanism. We used a dextran sulfate sodium (DSS)-induced murine colitis model to test the anti-inflammatory efficacy of BTW. Clinical symptoms were scored by the disease activity index (DAI), and the colon length and pathological changes in colon tissue were also used to further evaluate the efficacy of BTW. Precisely how BTW affected immune function and the intestinal barrier of UC mice was also examined. BTW significantly reduced DAI score and colonic pathological damage. BTW regulated the balance between T helper (Th)17 and regulatory T (Treg) cells, decreased interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, and increased IL-10 levels. BTW reduced intestinal permeability of UC mice, increased expression of tight junction proteins (occludin and zonula occludens-1), and decreased expression of phospho-nuclear factor (p-NF)-κB and phospho-extracellular signal-regulated kinase (p-ERK) in the colon. BTW inhibited the ERK/p-NF-κB signaling pathway and suppressed expression of cyclo-oxygenase-2 and inducible NO synthase in lipopolysaccharide-activated RAW 264.7 cells. BTW significantly promoted the synthesis of short-chain fatty acids in the gut, particularly acetate, propionate, isobutyric acid, and isovalerate. The results suggest that BTW can protect against DSS-induced UC. The mechanism may be partially attributed to regulating the balance of Th17/Treg cells and restoring the intestinal epithelial barrier.
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Affiliation(s)
- Zhiwei Miao
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Liping Chen
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Hui Feng
- Internal Medicine Department of Traditional Chinese Medicine, Zhongda Hospital Affiliated to Southeast University, Nanjing, China
| | - Mingjia Gu
- Department of Nephrology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Jing Yan
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yi Xu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bai Ye
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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31
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Mahapatro M, Erkert L, Becker C. Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut. Cells 2021; 10:cells10010111. [PMID: 33435303 PMCID: PMC7827439 DOI: 10.3390/cells10010111] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/28/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.
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32
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Liu H, Li T, Zhong S, Yu M, Huang W. Intestinal epithelial cells related lncRNA and mRNA expression profiles in dextran sulphate sodium-induced colitis. J Cell Mol Med 2021; 25:1060-1073. [PMID: 33300279 PMCID: PMC7812259 DOI: 10.1111/jcmm.16174] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/10/2020] [Accepted: 11/22/2020] [Indexed: 12/15/2022] Open
Abstract
Intestinal epithelial barrier damage caused by intestinal epithelial cells (IECs) dysfunction plays a crucial role in the pathogenesis and development of inflammatory bowel disease (IBD). Recently, some studies have suggested the emerging role of long non-coding RNAs (lncRNAs) in IBD. The aim of this study was to reveal lncRNAs and mRNA expression profiles in IECs from a mouse model of colitis and to expand our understanding in the intestinal epithelial barrier regulation. IECs from the colons of wild-type mice and dextran sulphate sodium (DSS)-induced mice were isolated for high-throughput RNA-sequencing. A total of 254 up-regulated and 1013 down-regulated mRNAs and 542 up-regulated and 766 down-regulated lncRNAs were detected in the DSS group compared with the Control group. Four mRNAs and six lncRNAs were validated by real-time quantitative PCR. Function analysis showed that dysregulated mRNAs participated in TLR7 signalling pathway, IL-1 receptor activity, BMP receptor binding and IL-17 signalling pathway. Furthermore, the possibility of indirect interactions between differentially expressed mRNAs and lncRNAs was illustrated by the competing endogenous RNA (ceRNA) network. LncRNA ENSMUST00000128026 was predicted to bind to mmu-miR-6899-3p, regulating Dnmbp expression. LncRNA NONMMUT143162.1 was predicted to competitively bind to mmu-miR-6899-3p, regulating Tnip3 expression. Finally, the protein-protein interaction (PPI) network analysis was constructed with 311 nodes and 563 edges. And the highest connectivity degrees were Mmp9, Fpr2 and Ccl3. These results provide novel insights into the functions of lncRNAs and mRNAs involved in the regulation of the intestinal epithelial barrier.
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Affiliation(s)
- Huan Liu
- The Precision Medicine InstituteThe Third Affiliated HospitalSouthern Medical UniversityGuangzhouChina
- Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Teming Li
- Department of General SurgeryXinqiao HospitalArmy Medical UniversityChongqingChina
| | - Shizhen Zhong
- Guangdong Engineering Research Center for Translation of Medical 3D Printing ApplicationGuangdong Provincial Key Laboratory of Medical BiomechanicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Min Yu
- Department of General SurgeryXinqiao HospitalArmy Medical UniversityChongqingChina
| | - Wenhua Huang
- The Precision Medicine InstituteThe Third Affiliated HospitalSouthern Medical UniversityGuangzhouChina
- Guangdong Engineering Research Center for Translation of Medical 3D Printing ApplicationGuangdong Provincial Key Laboratory of Medical BiomechanicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
- Pathological Diagnosis and Research CenterAffiliated Hospital of Guangdong Medical UniversityZhanjiangChina
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33
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Westfall S, Caracci F, Zhao D, Wu QL, Frolinger T, Simon J, Pasinetti GM. Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors. Brain Behav Immun 2021; 91:350-368. [PMID: 33096252 PMCID: PMC7986984 DOI: 10.1016/j.bbi.2020.10.013] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/07/2020] [Accepted: 10/10/2020] [Indexed: 02/08/2023] Open
Abstract
Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and behavioral abnormalities. There are both peripheral and brain region-specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of stress-induced psychological impairment. This study shows that a combination of probiotics and polyphenol-rich prebiotics, a synbiotic, attenuates the chronic-stress induced inflammatory responses in the ileum and the prefrontal cortex promoting resilience to the consequent depressive- and anxiety-like behaviors in male mice. Pharmacokinetic studies revealed that this effect may be attributed to specific synbiotic-produced metabolites including 4-hydroxyphenylpropionic, 4-hydroxyphenylacetic acid and caffeic acid. Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the prefrontal cortex and hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic's effect on the ileum's inflammatory response to stress. Synbiotic treatment indiscriminately attenuated the stress-induced immune and behavioral aberrations in both the ileum and the brain while in a gut-immune co-culture model, the synbiotic-specific metabolites promoted anti-inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic-stress induced behavioral impairments while defining a putative mechanism of gut-microbiota host interaction for modulating the peripheral and brain immune systems.
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Affiliation(s)
- Susan Westfall
- Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA
| | - Francesca Caracci
- Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA
| | - Danyue Zhao
- Department of Plant Biology, Rutgers University, New Brunswick, NJ, USA
| | - Qing-li Wu
- Department of Plant Biology, Rutgers University, New Brunswick, NJ, USA
| | - Tal Frolinger
- Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA
| | - James Simon
- Department of Plant Biology, Rutgers University, New Brunswick, NJ, USA
| | - Giulio Maria Pasinetti
- Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA; Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
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Sun T, Nguyen A, Gommerman JL. Dendritic Cell Subsets in Intestinal Immunity and Inflammation. THE JOURNAL OF IMMUNOLOGY 2020; 204:1075-1083. [PMID: 32071090 DOI: 10.4049/jimmunol.1900710] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/11/2019] [Indexed: 12/21/2022]
Abstract
The mammalian intestine is a complex environment that is constantly exposed to Ags derived from food, microbiota, and metabolites. Intestinal dendritic cells (DC) have the responsibility of establishing oral tolerance against these Ags while initiating immune responses against mucosal pathogens. We now know that DC are a heterogeneous population of innate immune cells composed of classical and monocyte-derived DC, Langerhans cells, and plasmacytoid DC. In the intestine, DC are found in organized lymphoid tissues, such as the mesenteric lymph nodes and Peyer's patches, as well as in the lamina propria. In this Brief Review, we review recent work that describes a division of labor between and collaboration among gut DC subsets in the context of intestinal homeostasis and inflammation. Understanding relationships between DC subtypes and their biological functions will rationalize oral vaccine design and will provide insights into treatments that quiet pathological intestinal inflammation.
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Affiliation(s)
- Tian Sun
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada
| | - Albert Nguyen
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada
| | - Jennifer L Gommerman
- Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada
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35
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Moreira Lopes TC, Mosser DM, Gonçalves R. Macrophage polarization in intestinal inflammation and gut homeostasis. Inflamm Res 2020; 69:1163-1172. [PMID: 32886145 DOI: 10.1007/s00011-020-01398-y] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 07/21/2020] [Accepted: 08/30/2020] [Indexed: 12/19/2022] Open
Abstract
Gut homeostasis is a process that requires a prudent balance of host responses to the beneficial enteric microbial community and the pathogenic stimuli that can arise. The lack of this balance in the intestine can result in inflammatory bowel diseases, where the immune system dysfunctions leading to exacerbated inflammatory responses. In this process, macrophages are considered to play a pivotal role. In this review, we describe the important role of macrophages in maintaining intestinal homeostasis and we discuss how altered macrophage function may lead to inflammatory bowel diseases. The plasticity of macrophages during the gut inflammatory response shows the broad role of these cells in orchestrating not only the onset of inflammation but also its termination as well as healing and repair. Indeed, the state of macrophage polarization can be the key factor in defining the resolution or the progression of inflammation and disease. Here, we discuss the different populations of macrophages and their implication in development, propagation, control and resolution of inflammatory bowel diseases.
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Affiliation(s)
- Tamara Cristina Moreira Lopes
- Laboratório de Biologia de Macrófagos e Monócitos, Departamento de Patologia Geral, Instituto de Ciências Biológicas-Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil
| | - David M Mosser
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA
| | - Ricardo Gonçalves
- Laboratório de Biologia de Macrófagos e Monócitos, Departamento de Patologia Geral, Instituto de Ciências Biológicas-Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil.
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36
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Mariana N, Asadul Isl A, Hatta M, Fransiscus H. IL23 mRNA Expression in Hirschsprung-Associated Enterocolitis. JOURNAL OF MEDICAL SCIENCES 2020. [DOI: 10.3923/jms.2020.39.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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37
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Fieldhouse KA, Ukaibe S, Crowley EL, Khanna R, O’Toole A, Gooderham MJ. Inflammatory bowel disease in patients with psoriasis treated with interleukin-17 inhibitors. Drugs Context 2020; 9:2020-2-1. [PMID: 32362930 PMCID: PMC7185907 DOI: 10.7573/dic.2020-2-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Interleukin 17 (IL-17) inhibitors provide an excellent treatment option for patients with psoriasis and psoriatic arthritis, resulting in high levels of efficacy for skin clearance and joint improvement. Safety has also been established in clinical trials for this group of biologic agents; however, rare case reports of exacerbation or induction of inflammatory bowel disease (IBD) have been reported in the literature. No causal relationship has been established. When IL-17 inhibitors were investigated for the management of IBD, no benefit was found and worsening of disease was noted for some patients. IBD is more common in patients with psoriasis and, therefore, it remains unknown if these drugs cause de novo IBD or if the reported cases of IBD in patients on IL-17 therapy is due to the background risk in this predisposed population who may have already had an underlying or subclinical disease. METHODS/RESULTS A literature search was conducted for the terms 'IL-17 inhibitor,' 'ixekizumab,' 'secukinumab,' 'brodalumab' and 'inflammatory bowel disease,' 'ulcerative colitis,' and 'Crohn's disease' in PubMed and Google Scholar. Cases of new-onset or exacerbation of IBD were identified in the literature along with postmarketing pharmacovigilance data. These cases will be reviewed in this paper. CONCLUSIONS IL-17 inhibitors have proven efficacy for the treatment of psoriasis and psoriatic arthritis with a strong safety profile. However, rare cases of IBD onset and exacerbation in patients on IL-17 inhibitors have been reported in the literature, highlighting the need to select patients and therapeutic choices appropriately when treating this population.
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Affiliation(s)
- Keira A Fieldhouse
- SKiN Centre for Dermatology, 775 Monaghan Road South, Peterborough, ON K9J 5K2, Canada
- Trent University, 1600 W Bank Dr, Peterborough, ON K9J 0G2, Canada
| | - Samantha Ukaibe
- Trent University, 1600 W Bank Dr, Peterborough, ON K9J 0G2, Canada
| | - Erika L Crowley
- SKiN Centre for Dermatology, 775 Monaghan Road South, Peterborough, ON K9J 5K2, Canada
- Trent University, 1600 W Bank Dr, Peterborough, ON K9J 0G2, Canada
| | - Reena Khanna
- University of Western Ontario, London, ON N6A 3K7, Canada
| | - Ashley O’Toole
- SKiN Centre for Dermatology, 775 Monaghan Road South, Peterborough, ON K9J 5K2, Canada
- Probity Medical Research, 139 Union St E, Waterloo, ON N2J 1C4, Canada
| | - Melinda J Gooderham
- SKiN Centre for Dermatology, 775 Monaghan Road South, Peterborough, ON K9J 5K2, Canada
- Probity Medical Research, 139 Union St E, Waterloo, ON N2J 1C4, Canada
- Queen’s University, 99 University Ave, Kingston, ON K7L 3N6, Canada
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38
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Chen Q, He Q, Xiu W, Chen Y, Guo Z. miR-340 affects sauchinone inhibition of Th17 cell differentiation and promotes intestinal inflammation in inflammatory bowel disease. Biochem Biophys Res Commun 2020; 526:1157-1163. [PMID: 32321642 DOI: 10.1016/j.bbrc.2020.04.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/10/2020] [Indexed: 12/30/2022]
Abstract
The pathogenesis of inflammation bowel disease (IBD) involves exaggerated effector T cell responses and impaired regulatory T cell functions. We previously found that sauchinone (SAU) ameliorated experimental colitis via facilitating Th17 cell production of IL-10, but how SAU regulated Th17 cell differentiation remains unknown. MicroRNAs (miR) have been recognized as a crucial regulator of T cell biology and play a considerable role in IBD. Here, we demonstrated that SAU significantly suppressed miR-340 expression in Th17 cells, and enforced miR-340 expression abrogated SAU inhibition of Th17 differentiation. miR-340 itself was found to facilitate Th17 differentiation, especially the pathogenic "Th1-like" subset. In human IBD, miR-340 was intimately correlated with the disease severity. SAU markedly decreased miR-340 in the inflamed mucosa tissues from IBD patients. Scaffold/matrix-associated region-binding protein 1 (SMAR1) was identified as a target gene of miR-340. We revealed that blockade of miR-340 significantly reduced mucosal damage and Th17 responses in the lamina propria in a mouse colitis model. Our findings suggest that miR-340 negatively affects SAU inhibition of Th17 differentiation and might play a crucial role in the regulation of pathogenic "Th1-like" Th17 cell generation, which might serve as a novel therapeutic target of IBD.
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Affiliation(s)
- Qinyuan Chen
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qinyu He
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Wenbo Xiu
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China; Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanxi Chen
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
| | - Zhenzhen Guo
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China; Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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39
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Abstract
Interleukin (IL)-10 is an essential anti-inflammatory cytokine and functions as a negative regulator of immune responses to microbial antigens. IL-10 is particularly important in maintaining the intestinal microbe-immune homeostasis. Loss of IL-10 promotes the development of inflammatory bowel disease (IBD) as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions more generally to prevent excessive inflammation during the course of infection. Although IL-10 can be produced by virtually all cells of the innate and adaptive immune system, T cells constitute a non-redundant source for IL-10 in many cases. The various roles of T cell-derived IL-10 will be discussed in this review. Given that IL-10 is at the center of maintaining the delicate balance between effective immunity and tissue protection, it is not surprising that IL-10 expression is highly dynamic and tightly regulated. We summarize the environmental signals and molecular pathways that regulate IL-10 expression. While numerous studies have provided us with a deep understanding of IL-10 biology, the majority of findings have been made in murine models, prompting us to highlight gaps in our knowledge about T cell-derived IL-10 in the human system.
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40
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Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice. Mucosal Immunol 2019; 12:930-944. [PMID: 31105269 PMCID: PMC6599481 DOI: 10.1038/s41385-019-0170-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/05/2019] [Accepted: 04/13/2019] [Indexed: 02/06/2023]
Abstract
Gut microbial translocation contributes to alcoholic hepatitis. Using a mouse model of alcoholic hepatitis, we investigated the effects of chronic alcohol plus binge and found increased abundance of Paneth cells and IL-17A in the proximal small intestine (PSI). Alcohol increased IL-17A production and pro-apoptotic signaling evidenced by Bax, Bim, caspase-3, and caspase-8 increases via endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) upregulation; this was prevented by the ER stress inhibitor, 4-PBA, in isolated crypts in vitro and in vivo. Mechanistically, IL-17 augmented alcohol-induced ER stress in isolated crypts. In vivo IL-17A blocking antibody administration in alcohol-treated mice attenuated ER stress-mediated apoptosis and IL-18 induction and prevented alcohol-induced impairment of tight junctions in the PSI and LPS translocation to the liver. Acute-on-chronic alcohol resulted in inflammasome activation, caspase-1 cleavage, and IL-18 production in the PSI. In vivo treatment with antibiotics or 4-PBA prevented CHOP upregulation and inflammasome activation. Our data suggest that alcohol upregulates innate immune mechanisms by increasing Paneth cell numbers and IL-17A release contributing to apoptosis amplification, inflammasome activation, and gut leakiness in the PSI. Binge alcohol-induced Paneth cell expansion, ER stress, and inflammasome activation in the PSI are modulated by the gut microbiome.
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Ji J, Ge X, Chen Y, Zhu B, Wu Q, Zhang J, Shan J, Cheng H, Shi L. Daphnetin ameliorates experimental colitis by modulating microbiota composition and T reg/T h17 balance. FASEB J 2019; 33:9308-9322. [PMID: 31145641 DOI: 10.1096/fj.201802659rr] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel diseases (IBDs) are characterized by chronic pathologies associated with extensive gut dysbiosis and intestinal inflammation. Hence, endeavors to improve the inflammatory pathology by manipulating gut microbiota are ongoing. Daphnetin (DAPH) is a coumarin derivative extracted from Daphne odora var with anti-inflammatory and immune-regulatory properties that has been widely used in treating inflammatory disorders. Herein, we showed that DAPH remarkably alleviated experimental colitis by reducing colonic inflammation, improving colonic integrity, and reestablishing immune and metabolic homeostasis in the inflicted intestines. Our analysis showed that DAPH modified the composition of gut microbiota and altered the metabolic profiles in dextran sulfate sodium-treated mice. In particular, this agent significantly elevated the abundance of short-chain fatty acid (SCFA)-producing gut microbiota, causatively related with the enhanced development of Treg cells and the reduced proinflammatory Th17 cell differentiation. More critically, the protective effect of DAPH was shown to be transmissible among colitic mice through cohousing or fecal microbiota transplantation, further substantiating the importance of SCFA-producing gut microbiota in DAPH action. We thus for the first time reveal the potential of DAPH in resetting the gut microbiome and reestablishing immune homeostasis in colitic mice, which may have clinical implications for treating IBD.-Ji, J., Ge, X., Chen, Y., Zhu, B., Wu, Q., Zhang, J., Shan, J., Cheng, H., Shi, L. Daphnetin ameliorates experimental colitis by modulating microbiota composition and Treg/Th17 balance.
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Affiliation(s)
- Jianjian Ji
- Key Laboratory of Inflammation and Immunoregulation, School of Medical and Life Science, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoyin Ge
- Key Laboratory of Inflammation and Immunoregulation, School of Medical and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yugen Chen
- Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bo Zhu
- Key Laboratory of Inflammation and Immunoregulation, School of Medical and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qinan Wu
- Collaborative Innovation Centers of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
| | - Junfeng Zhang
- Key Laboratory of Inflammation and Immunoregulation, School of Medical and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinjun Shan
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haibo Cheng
- The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Liyun Shi
- Key Laboratory of Inflammation and Immunoregulation, School of Medical and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
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Vorobjova T, Tagoma A, Oras A, Alnek K, Kisand K, Talja I, Uibo O, Uibo R. Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa. J Immunol Res 2019; 2019:6179243. [PMID: 31214623 PMCID: PMC6535873 DOI: 10.1155/2019/6179243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/08/2019] [Accepted: 04/24/2019] [Indexed: 02/08/2023] Open
Abstract
Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.
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Affiliation(s)
- Tamara Vorobjova
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Aili Tagoma
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Astrid Oras
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kristi Alnek
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Kalle Kisand
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Ija Talja
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Oivi Uibo
- Department of Pediatrics, Institute of Clinical Medicine, University of Tartu, Estonia
- Children's Clinic, Tartu University Hospital, Tartu, Estonia
| | - Raivo Uibo
- Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 51014 Tartu, Estonia
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Mathur R, Alam MM, Zhao XF, Liao Y, Shen J, Morgan S, Huang T, Lee H, Lee E, Huang Y, Zhu X. Induction of autophagy in Cx3cr1 + mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis. Mucosal Immunol 2019; 12:612-623. [PMID: 30765845 PMCID: PMC6927046 DOI: 10.1038/s41385-019-0146-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 01/21/2019] [Accepted: 01/27/2019] [Indexed: 02/04/2023]
Abstract
Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn's disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)-23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG-/- mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.
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Affiliation(s)
- Ramkumar Mathur
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA.
- The IBD Center, Division of Gastroenterology, Department of Medicine, Albany Medical College, Albany, NY, 12208, USA.
| | - Mahabub Maraj Alam
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Xiao-Feng Zhao
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Yuan Liao
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA
| | - Jeffrey Shen
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA
| | - Shannon Morgan
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Tingting Huang
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - HwaJeong Lee
- Department of Pathology, Albany Medical College, Albany, NY, 12208, USA
| | - Edward Lee
- Department of Surgery, Albany Medical College, Albany, NY, 12208, USA
| | - Yunfei Huang
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, 12208, USA
| | - Xinjun Zhu
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208, USA.
- The IBD Center, Division of Gastroenterology, Department of Medicine, Albany Medical College, Albany, NY, 12208, USA.
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Kermarrec L, Eissa N, Wang H, Kapoor K, Diarra A, Gounni AS, Bernstein CN, Ghia J. Semaphorin-3E attenuates intestinal inflammation through the regulation of the communication between splenic CD11C + and CD4 + CD25 - T-cells. Br J Pharmacol 2019; 176:1235-1250. [PMID: 30736100 PMCID: PMC6468259 DOI: 10.1111/bph.14614] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 01/02/2019] [Accepted: 01/15/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE An alteration in the communication between the innate and adaptive immune cells is a hallmark of ulcerative colitis (UC). Semaphorin-3E (SEMA3E), a secreted guidance protein, regulates various immune responses. EXPERIMENTAL APPROACH We investigated the expression of SEMA3E in colonic biopsies of active UC patients and its mechanisms in Sema3e-/- mice using an experimental model of UC. KEY RESULTS SEMA3E level was decreased in active UC patients and negatively correlated with pro-inflammatory mediators. Colonic expression of SEMA3E was reduced in colitic Sema3e+/+ mice, and recombinant (rec-) Plexin-D1 treatment exacerbated disease severity. In vivo rec-SEMA3E treatment restored SEMA3E level in colitic Sema3e+/+ mice. In Sema3e-/- mice, disease severity was increased, and rec-SEMA3E ameliorated these effects. Lack of Sema3e increased the expression of CD11c and CD86 markers. Colitic Sema3e-/- splenocytes and splenic CD11c+ cells produced more IL-12/23 and IFN-γ compared to Sema3e+/+ , and rec-SEMA3E reduced their release as much as NF-κB inhibitors, whereas an NF-κB activator increased their production and attenuated the effect of rec-SEMA3E. Colitic Sema3e-/- splenic CD11c+ /CD4+ CD25- T-cell co-cultures produced higher concentrations of IFN-γ and IL-17 when compared to colitic Sema3e+/+ splenic cell co-cultures, and rec-SEMA3E decreased these effects. In vitro, anti-IL-12p19 and -12p35 antibodies and rec-IL-12 and -23 treatment confirmed the crosstalk between CD11c+ and CD4+ CD25- T-cells. CONCLUSION AND IMPLICATIONS SEMA3E is reduced in colitis and modulates colonic inflammation by regulating the interaction between CD11c+ and CD4+ CD25- T-cells via an NF-κB-dependent mechanism. Thus, SEMA3E could be a potential therapeutic target for UC patients.
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Affiliation(s)
| | - Nour Eissa
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
- Children Research Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegManitobaCanada
- Department of Internal Medicine Section of Gastroenterology, IBD Clinical and Research CentreUniversity of ManitobaWinnipegManitobaCanada
| | - Hongxing Wang
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | - Kunal Kapoor
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | - Abdoulaye Diarra
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | | | - Charles N. Bernstein
- Department of Internal Medicine Section of Gastroenterology, IBD Clinical and Research CentreUniversity of ManitobaWinnipegManitobaCanada
| | - Jean‐Eric Ghia
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
- Children Research Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegManitobaCanada
- Department of Internal Medicine Section of Gastroenterology, IBD Clinical and Research CentreUniversity of ManitobaWinnipegManitobaCanada
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45
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Moschen AR, Tilg H, Raine T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat Rev Gastroenterol Hepatol 2019; 16:185-196. [PMID: 30478416 DOI: 10.1038/s41575-018-0084-8] [Citation(s) in RCA: 322] [Impact Index Per Article: 53.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn's disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.
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Affiliation(s)
- Alexander R Moschen
- Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria. .,Department of Medicine, Division of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria.
| | - Herbert Tilg
- Department of Medicine, Division of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
| | - Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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46
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Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:177-201. [PMID: 30612460 DOI: 10.1142/s0192415x19500095] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn’s disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4[Formula: see text]) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.
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Affiliation(s)
- Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China
| | - Qiyuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xiaocheng Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, P. R. China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
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47
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Hoeppli RE, MacDonald KN, Leclair P, Fung VCW, Mojibian M, Gillies J, Rahavi SMR, Campbell AIM, Gandhi SK, Pesenacker AM, Reid G, Lim CJ, Levings MK. Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions. Am J Transplant 2019; 19:62-76. [PMID: 29766641 DOI: 10.1111/ajt.14936] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 04/17/2018] [Accepted: 05/06/2018] [Indexed: 01/25/2023]
Abstract
Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4β7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.
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Affiliation(s)
- R E Hoeppli
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - K N MacDonald
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.,Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
| | - P Leclair
- Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - V C W Fung
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - M Mojibian
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - J Gillies
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - S M R Rahavi
- Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - A I M Campbell
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - S K Gandhi
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - A M Pesenacker
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - G Reid
- Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - C J Lim
- Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - M K Levings
- Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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48
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Jie Z, Yang JY, Gu M, Wang H, Xie X, Li Y, Liu T, Zhu L, Shi J, Zhang L, Zhou X, Joo D, Brightbill HD, Cong Y, Lin D, Cheng X, Sun SC. NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis. Nat Immunol 2018; 19:1224-1235. [PMID: 30250187 PMCID: PMC6195481 DOI: 10.1038/s41590-018-0206-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 08/13/2018] [Indexed: 12/12/2022]
Abstract
Dendritic cells (DCs) play an integral role in regulating mucosal immunity and homeostasis, but the signaling network mediating this function of DCs is poorly defined. We identified the noncanonical NF-κB-inducing kinase (NIK) as a crucial mediator of mucosal DC function. DC-specific NIK deletion impaired intestinal immunoglobulin A (IgA) secretion and microbiota homeostasis, rendering mice sensitive to an intestinal pathogen, Citrobacter rodentium. DC-specific NIK was required for expression of the IgA transporter polymeric immunoglobulin receptor (pIgR) in intestinal epithelial cells, which in turn relied on the cytokine IL-17 produced by TH17 cells and innate lymphoid cells (ILCs). NIK-activated noncanonical NF-κB induced expression of IL-23 in DCs, contributing to the maintenance of TH17 cells and type 3 ILCs. Consistent with the dual functions of IL-23 and IL-17 in mucosal immunity and inflammation, NIK deficiency also ameliorated colitis induction. Thus, our data suggest a pivotal role for the NIK signaling axis in regulating DC functions in intestinal immunity and homeostasis.
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Affiliation(s)
- Zuliang Jie
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jin-Young Yang
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Meidi Gu
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hui Wang
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Xiaoping Xie
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yanchuan Li
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ting Liu
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Laboratory Medicine, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Lele Zhu
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianhong Shi
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Central Laboratory, Affiliated Hospital of Hebei University, Baoding, China
| | - Lingyun Zhang
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaofei Zhou
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Donghyun Joo
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hans D Brightbill
- Department of Immunology, Genentech, Inc., South San Francisco, CA, USA
| | - Yingzi Cong
- Department of Pathology and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Daniel Lin
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xuhong Cheng
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shao-Cong Sun
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
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49
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Fernández-Clotet A, Castro-Poceiro J, Panés J. Tofacitinib for the treatment of ulcerative colitis. Expert Rev Clin Immunol 2018; 14:881-892. [DOI: 10.1080/1744666x.2018.1532291] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Agnès Fernández-Clotet
- Inflammatory Bowel Disease Group, Institut d’Investigacions Biomètiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Jesús Castro-Poceiro
- Inflammatory Bowel Disease Group, Institut d’Investigacions Biomètiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Department of Gastroenterology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Julián Panés
- Inflammatory Bowel Disease Group, Institut d’Investigacions Biomètiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Department of Gastroenterology, Hospital Clínic de Barcelona, Barcelona, Spain
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50
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Dubé PE, Liu CY, Girish N, Washington MK, Polk DB. Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice. Sci Rep 2018; 8:9119. [PMID: 29904166 PMCID: PMC6002410 DOI: 10.1038/s41598-018-27353-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/30/2018] [Indexed: 12/15/2022] Open
Abstract
Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity ("early"), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation ("late") increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.
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Affiliation(s)
- Philip E Dubé
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Taconic Biosciences, Hudson, NY, USA
| | - Cambrian Y Liu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - M Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA.
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
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