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Pastras P, Aggeletopoulou I, Papantoniou K, Triantos C. Targeting the IL-23 Receptor Gene: A Promising Approach in Inflammatory Bowel Disease Treatment. Int J Mol Sci 2025; 26:4775. [PMID: 40429917 DOI: 10.3390/ijms26104775] [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: 04/15/2025] [Revised: 05/09/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's Disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. A key component of the inflammatory pathway in IBD is interleukin 23 (IL-23), which promotes the differentiation and maintenance of Th17 cells. These cells are major contributors to intestinal inflammation and the release of pro-inflammatory cytokines. A dysregulated IL-23/Th17 axis can lead to excessive gut inflammation. Notably, IL-23 affects Th17 cell responses differently in UC and CD, fostering IL-17 production in UC and interferon-gamma (IFN-γ) production in CD. Genetic studies have pinpointed specific variants of the IL-23 receptor (IL23R) gene that confer protection against IBD. The R381Q (rs11209026) variant has been linked to a reduced risk of developing both CD and UC. Additionally, other variants, such as G149R (rs76418789) and V362I (rs41313262), inhibit IL23R function by disrupting intracellular trafficking and protein stability. This disruption results in decreased phosphorylation of downstream signal transducers, such as STAT3 and STAT4, and reduced IL23R expression on the cell surface, ultimately dampening the activation of pro-inflammatory pathways. The protective effects of these genetic variants underscore the IL-23/IL23R pathway as a significant therapeutic target in IBD management. Therapies designed to modulate this pathway have the potential to reduce pro-inflammatory cytokine production and enhance anti-inflammatory mechanisms. Ongoing research into the IL23R gene and its variants continues to provide valuable insights, paving the way for more targeted and effective treatments for IBD patients.
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Affiliation(s)
- Ploutarchos Pastras
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Konstantinos Papantoniou
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
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2
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Pfeifle A, Zhang W, Cao J, Thulasi Raman SN, Anderson-Duvall R, Tamming L, Gravel C, Coatsworth H, Chen W, Johnston MJW, Sauve S, Rosu-Myles M, Wang L, Li X. Novel recombinant vaccinia virus-vectored vaccine affords complete protection against homologous Borrelia burgdorferi infection in mice. Emerg Microbes Infect 2024; 13:2399949. [PMID: 39221484 PMCID: PMC11486199 DOI: 10.1080/22221751.2024.2399949] [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: 06/13/2024] [Revised: 08/09/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
The rising prevalence of Lyme disease (LD) in North America and Europe has emerged as a pressing public health concern. Despite the availability of veterinary LD vaccines, no vaccine is currently available for human use. Outer surface protein C (OspC) found on the outer membrane of the causative agent, Borrelia burgdorferi, has been identified as a promising target for LD vaccine development due to its sustained expression during mammalian infection. However, the efficacy and immunological mechanisms of LD vaccines solely targeting OspC are not well characterized. In this study, we developed an attenuated Vaccinia virus (VV) vectored vaccine encoding type A OspC (VV-OspC-A). Two doses of the VV-OspC-A vaccine conferred complete protection against homologous B. burgdorferi challenge in mice. Furthermore, the candidate vaccine also prevented the development of carditis and lymph node hyperplasia associated with LD. When investigating the humoral immune response to vaccination, VV-OspC-A was found to induce a robust antibody response predominated by the IgG2a subtype, indicating a Th1-bias. Using a novel quantitative flow cytometry assay, we also determined that elicited antibodies were capable of inducing antibody-dependent cellular phagocytosis in vitro. Finally, we demonstrated that VV-OspC-A vaccination generated a strong antigen-specific CD4+ T-cell response characterized by the secretion of numerous cytokines upon stimulation of splenocytes with OspC peptides. This study suggests a promising avenue for LD vaccine development utilizing viral vectors targeting OspC and provides insights into the immunological mechanisms that confer protection against B. burgdorferi infection.
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MESH Headings
- Animals
- Vaccinia virus/genetics
- Vaccinia virus/immunology
- Lyme Disease/prevention & control
- Lyme Disease/immunology
- Borrelia burgdorferi/immunology
- Borrelia burgdorferi/genetics
- Mice
- Bacterial Outer Membrane Proteins/immunology
- Bacterial Outer Membrane Proteins/genetics
- Antibodies, Bacterial/blood
- Antibodies, Bacterial/immunology
- Female
- Antigens, Bacterial/immunology
- Antigens, Bacterial/genetics
- Vaccines, Synthetic/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/genetics
- Genetic Vectors
- Immunoglobulin G/blood
- Bacterial Vaccines/immunology
- Bacterial Vaccines/genetics
- Bacterial Vaccines/administration & dosage
- Lyme Disease Vaccines/immunology
- Lyme Disease Vaccines/administration & dosage
- Disease Models, Animal
- CD4-Positive T-Lymphocytes/immunology
- Vaccines, Attenuated/immunology
- Vaccines, Attenuated/administration & dosage
- Vaccines, Attenuated/genetics
- Phagocytosis
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Affiliation(s)
- Annabelle Pfeifle
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Wanyue Zhang
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Jingxin Cao
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
| | - Sathya N. Thulasi Raman
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
| | - Rose Anderson-Duvall
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Levi Tamming
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Caroline Gravel
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
| | - Heather Coatsworth
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
| | - Wangxue Chen
- Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada
| | - Michael J. W. Johnston
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
- Department of Chemistry, Carleton University, Ottawa, Canada
| | - Simon Sauve
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
| | - Michael Rosu-Myles
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Xuguang Li
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
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Yamazaki F, Kobayashi K, Mochizuki J, Sashihara T. Interleukin-22 enhanced the mucosal barrier and inhibited the invasion of Salmonella enterica in human-induced pluripotent stem cell-derived small intestinal epithelial cells. FEMS Microbiol Lett 2024; 371:fnae006. [PMID: 38268488 DOI: 10.1093/femsle/fnae006] [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: 09/28/2023] [Revised: 01/10/2024] [Accepted: 01/23/2024] [Indexed: 01/26/2024] Open
Abstract
Human-induced pluripotent stem cell-derived small intestinal epithelial cell (hiPSC-SIEC) monolayers are useful in vitro models for evaluating the gut mucosal barrier; however, their reactivity to cytokines, which are closely related to the regulation of mucosal barrier function, remains unclear. Interleukin (IL)-22 is a cytokine that contributes to regulate the mucosal barrier in the intestinal epithelia. Using microarray and gene set enrichment analysis, we found that hiPSC-SIEC monolayers activate the immune response and enhance the mucosal barrier in response to IL-22. Moreover, hiPSC-SIEC monolayers induced the gene expression of antimicrobials, including the regenerating islet-derived protein 3 family. Furthermore, IL-22 stimulation upregulated Mucin 2 secretion and gene expression of an enzyme that modifies sugar chains, suggesting alteration of the state of the mucus layer of hiPSC-SIEC monolayers. To evaluate its physiological significance, we measured the protective activity against Salmonella enterica subsp. enterica infection in hiPSC-SIEC monolayers and found that prestimulation with IL-22 reduced the number of viable intracellular bacteria. Collectively, these results suggest that hiPSC-SIEC monolayers enhance the mucosal barrier and inhibit infection by pathogenic bacteria in response to IL-22, as previously reported. These results can contribute to the further application of hiPSC-SIECs in evaluating mucosal barriers.
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Affiliation(s)
- Fuka Yamazaki
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
| | - Kyosuke Kobayashi
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
| | - Junko Mochizuki
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
| | - Toshihiro Sashihara
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co., Ltd, 1-29-1 Nanakuni, Hachioji, Tokyo 192-0919, Japan
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Moniruzzaman M, Rahman MA, Wang R, Wong KY, Chen ACH, Mueller A, Taylor S, Harding A, Illankoon T, Wiid P, Sajiir H, Schreiber V, Burr LD, McGuckin MA, Phipps S, Hasnain SZ. Interleukin-22 suppresses major histocompatibility complex II in mucosal epithelial cells. J Exp Med 2023; 220:e20230106. [PMID: 37695525 PMCID: PMC10494524 DOI: 10.1084/jem.20230106] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 05/22/2023] [Accepted: 08/18/2023] [Indexed: 09/12/2023] Open
Abstract
Major histocompatibility complex (MHC) II is dynamically expressed on mucosal epithelial cells and is induced in response to inflammation and parasitic infections, upon exposure to microbiota, and is increased in chronic inflammatory diseases. However, the regulation of epithelial cell-specific MHC II during homeostasis is yet to be explored. We discovered a novel role for IL-22 in suppressing epithelial cell MHC II partially via the regulation of endoplasmic reticulum (ER) stress, using animals lacking the interleukin-22-receptor (IL-22RA1), primary human and murine intestinal and respiratory organoids, and murine models of respiratory virus infection or with intestinal epithelial cell defects. IL-22 directly downregulated interferon-γ-induced MHC II on primary epithelial cells by modulating the expression of MHC II antigen A α (H2-Aα) and Class II transactivator (Ciita), a master regulator of MHC II gene expression. IL-22RA1-knockouts have significantly higher MHC II expression on mucosal epithelial cells. Thus, while IL-22-based therapeutics improve pathology in chronic disease, their use may increase susceptibility to viral infections.
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Affiliation(s)
- Md Moniruzzaman
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - M. Arifur Rahman
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Ran Wang
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Kuan Yau Wong
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Alice C.-H. Chen
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Alexandra Mueller
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Steven Taylor
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Alexa Harding
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Thishan Illankoon
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Percival Wiid
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Haressh Sajiir
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Veronika Schreiber
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
| | - Lucy D. Burr
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
- Department of Respiratory and Sleep Medicine, Mater Health, South Brisbane, Australia
| | - Michael A. McGuckin
- Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia
| | - Simon Phipps
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
- Respiratory Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Sumaira Z. Hasnain
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Immunopathology Group, Translational Research Institute, Mater Research Institute—The University of Queensland, Brisbane, Australia
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
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5
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Soleimanifar N, Assadiasl S, Alamolhoda MH, Nateghpour M, Arani MM, Sadr M, Mohebbi B, Mojtahedi H, Nicknam MH. Effect of Ramadan fasting on salivary IgA, serum IgA, IL-17, and IL-22 levels. Nutr Health 2023; 29:591-597. [PMID: 35404155 DOI: 10.1177/02601060221092203] [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] [Indexed: 11/16/2022]
Abstract
Background: nutritional factors might affect the number and function of immune cells for instance the production of cytokines and immunoglobulins. Ramadan fasting is intermittent abstinence from eating and drinking for almost four weeks. Aim: The present study aimed to investigate the influence of intermittent fasting on serum IgA, salivary IgA (sIgA), interleukin (IL)-17, and IL-22 levels. Methods: 40 healthy men aged 19-29 years were evaluated before and during the fourth week of Ramadan fasting for IgA levels by the nephelometric method as well as salivary IgA (sIgA), IL-17, and IL-22 amounts using enzyme-linked immunosorbent assay (ELISA). Results: serum IgA levels reduced significantly at the end of Ramadan fasting (225.8 ± 87 vs. 196 ± 70 mg/dl) (p-value<0.001); however, sIgA amounts did not differ between before and the last week of Ramadan. Serum IL-17 reduced significantly (2.93 ± 1.51 vs. 2.17 ± 1.33 pg/ml) (p-value = 0.006) whereas IL-22 levels remained approximately unchanged. Summary: four weeks of intermittent fasting during Ramadan reduced the serum levels of IgA and IL-17 but did not affect the production of sIgA and IL-22. These findings indicate a limited impact of intermittent fasting on mucosal immunity.
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Affiliation(s)
- Narjes Soleimanifar
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mehdi Nateghpour
- Research Center of Quran, Hadith and Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Sadr
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Mohebbi
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanieh Mojtahedi
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, Medicine School, Tehran University of Medical Sciences, Tehran, Iran
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da Silva EM, Yariwake VY, Alves RW, de Araujo DR, Andrade-Oliveira V. Crosstalk between incretin hormones, Th17 and Treg cells in inflammatory diseases. Peptides 2022; 155:170834. [PMID: 35753504 DOI: 10.1016/j.peptides.2022.170834] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/20/2022] [Accepted: 06/20/2022] [Indexed: 02/07/2023]
Abstract
Intestinal epithelial cells constantly crosstalk with the gut microbiota and immune cells of the gut lamina propria. Enteroendocrine cells, secrete hormones, such as incretin hormones, which participate in host physiological events, such as stimulating insulin secretion, satiety, and glucose homeostasis. Interestingly, evidence suggests that the incretin pathway may influence immune cell activation. Consequently, drugs targeting the incretin hormone signaling pathway may ameliorate inflammatory diseases such as inflammatory bowel diseases, cancer, and autoimmune diseases. In this review, we discuss how these hormones may modulate two subsets of CD4 + T cells, the regulatory T cells (Treg)/Th17 axis important for gut homeostasis: thus, preventing the development and progression of inflammatory diseases. We also summarize the main experimental and clinical findings using drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) signaling pathways and their great impact on conditions in which the Treg/Th17 axis is disturbed such as inflammatory diseases and cancer. Understanding the role of incretin stimulation in immune cell activation and function, might contribute to new therapeutic designs for the treatment of inflammatory diseases, autoimmunity, and tumors.
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Affiliation(s)
| | - Victor Yuji Yariwake
- Department of Immunology - Institute of Biomedical Sciences, University of São Paulo (USP), Brazil
| | - Renan Willian Alves
- Center for Natural and Human Sciences, Federal University of ABC (UFABC), Brazil
| | | | - Vinicius Andrade-Oliveira
- Paulista School of Medicine, Federal University of São Paulo (UNIFESP), Brazil; Department of Immunology - Institute of Biomedical Sciences, University of São Paulo (USP), Brazil; Center for Natural and Human Sciences, Federal University of ABC (UFABC), Brazil.
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7
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Yang J, Syed F, Xia Y, Sanyal A, Shah V, Chalasani N, Zheng X, Yu Q, Lou Y, Li W. Blood Biomarkers of Intestinal Epithelium Damage Regenerating Islet-derived Protein 3α and Trefoil Factor 3 Are Persistently Elevated in Patients with Alcoholic Hepatitis. Alcohol Clin Exp Res 2021; 45:720-731. [PMID: 33587293 PMCID: PMC8076084 DOI: 10.1111/acer.14579] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/11/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). METHODS Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. RESULTS At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. CONCLUSIONS Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.
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Affiliation(s)
- Jing Yang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Fahim Syed
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Ying Xia
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Xiaoqun Zheng
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yongliang Lou
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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8
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Fibi-Smetana S, Vaz C, Le Coz J, Ilic S, Berrios R, Schatzmayr G, Tanavde V, Grenier B. Research Note: Snapshot of the transcriptome via RNA sequencing in the ileum of broiler chickens fed subtherapeutic concentrations of avilamycin. Poult Sci 2020; 100:998-1003. [PMID: 33518154 PMCID: PMC7858091 DOI: 10.1016/j.psj.2020.11.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 11/25/2022] Open
Abstract
Antibiotics have played a critical role in sustaining and improving livestock production in the past decades, but the emergence of antimicrobial resistance has led several countries to ban or limit their use. Since then, in-feed alternatives have gained a lot of attention but the development of efficacious alternatives implies a better understanding of the mode of action of antibiotic growth promoters (AGP) when administered at subtherapeutic concentrations. In the present study, 120 broiler chickens per group (8 pens/group) were fed for 35 d with either basal feed (control group) or feed supplemented with avilamycin (AGP group; 10 g/1,000 kg of feed). At the end of the trial, the ileum from the small intestine of 5 birds per group was sampled, and RNA were isolated for profiling their transcriptome via RNA sequencing (RNA-Seq). As expected, the growth of chickens in the AGP group was significantly higher than in the control group. Overall, 66 differentially expressed genes (false discovery rate ≤ 0.05 and fold change ≥ 2 or ≤ −2) were found in the ileum of chickens fed avilamycin in comparison with the control group. The functional analysis showed reduced activity of genes related to signaling by interleukins, with IL-22, SOCS3, and certain antimicrobial peptides found multiple times in these pathways in the AGP group at day 35. In addition, higher activity was predicted in a module of genes related to lipid metabolism and transport in the avilamycin group. The use of RNA-Seq allowed a snapshot of the whole transcriptome at day 35 and aimed at delivering additional data on the host-centric hypothesis regarding the mode of action of AGP (i.e. immunomodulation, reduction of the immunological stress).
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Affiliation(s)
| | - Candida Vaz
- Bioinformatics Institute, Agency for Science Technology and Research (A∗STAR), Singapore 138671
| | - Jeremy Le Coz
- BIOMIN Research Center, BIOMIN Holding GmbH, 3430 Tulln, Austria
| | - Suzana Ilic
- BIOMIN Research Center, BIOMIN Holding GmbH, 3430 Tulln, Austria
| | - Roger Berrios
- BIOMIN Holding GmbH, Erber Campus 1, 3131 Getzersdorf, Austria
| | - Gerd Schatzmayr
- BIOMIN Research Center, BIOMIN Holding GmbH, 3430 Tulln, Austria
| | - Vivek Tanavde
- Bioinformatics Institute, Agency for Science Technology and Research (A∗STAR), Singapore 138671
| | - Bertrand Grenier
- BIOMIN Research Center, BIOMIN Holding GmbH, 3430 Tulln, Austria.
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9
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Fachi JL, Sécca C, Rodrigues PB, Mato FCPD, Di Luccia B, Felipe JDS, Pral LP, Rungue M, Rocha VDM, Sato FT, Sampaio U, Clerici MTPS, Rodrigues HG, Câmara NOS, Consonni SR, Vieira AT, Oliveira SC, Mackay CR, Layden BT, Bortoluci KR, Colonna M, Vinolo MAR. Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. J Exp Med 2020; 217:133544. [PMID: 31876919 PMCID: PMC7062529 DOI: 10.1084/jem.20190489] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/29/2019] [Accepted: 12/09/2019] [Indexed: 12/11/2022] Open
Abstract
Microbiota-derived acetate coordinates innate immune responses during intestinal Clostridium difficile infection through its cognate receptor FFAR2. Acetate accelerates early neutrophil recruitment and increases ILC3 expression of the IL-1 receptor, boosting ILC3 production of IL-22 in response to neutrophil-derived IL-1β. Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1β; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1β. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.
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Affiliation(s)
- José Luís Fachi
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.,Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO
| | - Cristiane Sécca
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO
| | - Patrícia Brito Rodrigues
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Felipe Cézar Pinheiro de Mato
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Blanda Di Luccia
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO
| | - Jaqueline de Souza Felipe
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Laís Passariello Pral
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marcella Rungue
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Victor de Melo Rocha
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Fabio Takeo Sato
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Ulliana Sampaio
- Department of Food Technology, School of Food Engineering, University of Campinas, Campinas, Brazil
| | | | - Hosana Gomes Rodrigues
- Laboratory of Nutrients & Tissue Repair, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | | | - Sílvio Roberto Consonni
- Department of Biochemistry & Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Angélica Thomaz Vieira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Sergio Costa Oliveira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Brian T Layden
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL.,Jesse Brown Veterans Medical Center, Chicago, IL
| | - Karina Ramalho Bortoluci
- Center for Cellular and Molecular Therapy, Federal University of São Paulo, Vl Clementino, São Paulo, Brazil
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO
| | - Marco Aurélio Ramirez Vinolo
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.,Experimental Medicine Research Cluster, Campinas, Brazil
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10
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Low JT, Christie M, Ernst M, Dumoutier L, Preaudet A, Ni Y, Griffin MDW, Mielke LA, Strasser A, Putoczki TL, O'Reilly LA. Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice. Gastroenterology 2020; 159:1444-1458.e15. [PMID: 32569771 DOI: 10.1053/j.gastro.2020.06.039] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Activity of nuclear factor κB transcription factors and signaling via signal transducer and activator of transcription (STAT) are frequently altered in gastric cancer cells. Mice lacking NFKB1 (Nfkb1-/- mice) develop invasive gastric cancer, and their gastric tissues have increased levels of cytokines, such as interleukin (IL) 6, IL22, IL11, and tumor necrosis factor (TNF), as well as increased activation of STAT1. We investigated whether these cytokines were required for STAT1 activation in gastric tissues of mice and critical for gastric tumorigenesis. METHODS We crossed Nfkb1-/- mice with Il6-/-, Il22-/-, Il11Rα-/-, and Tnf-/- mice. Stomach tissues from compound mutant mice were analyzed by histology, immunoblotting, and RNA sequencing. Lymphoid, myeloid, and epithelial cells were isolated from stomachs, and the levels of cytokines were determined by flow cytometric analysis. RESULTS Nfkb1-/- mice developed gastritis, oxyntic atrophy, gastric dysplasia, and invasive tumors, whereas Nfkb1-/-Stat1-/- mice did not, even when followed for as long as 2 years. The levels of Il6, Il11, Il22, and Tnf messenger RNA were increased in the body and antrum of the stomachs from Nfkb1-/- mice, from 3-6 months of age. However, Nfkb1-/-Il6-/-, Nfkb1-/-Il22-/-, and Nfkb1-/-Il11Rα-/- mice still developed gastric tumors, although the absence of IL11 receptor (IL11R) significantly reduced development of invasive gastric tumors. Stomachs from Nfkb1-/-Tnf-/- mice exhibited significantly less gastritis and oxyntic atrophy and fewer tumors than Nfkb1-/- mice. This correlated with reduced activation of STAT1 and STAT3 and fewer numbers of T cells and B cells infiltrating the gastric body. Loss of STAT1 or TNF significantly reduced expression of PD-L1 on epithelial and myeloid (CD11b+) cells in the gastric mucosa of Nfkb1-/- mice-indeed, to the levels observed on the corresponding cells from wild-type mice. CONCLUSIONS In studies of gastric tumor development in knockout mice, we found that loss of NFKB1 causes increased expression of TNF in the stomach and thereby drives activation of STAT1, resulting in an inflammatory immune response and the development of gastric cancer. IL11R appears to be required for the progression of gastric tumors to the invasive stage. These findings suggest that inhibitors of TNF, and possibly also inhibitors of IL11/IL11Rα, might be useful in the treatment of gastric cancer.
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Affiliation(s)
- Jun T Low
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Michael Christie
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia
| | | | - Adele Preaudet
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Yanhong Ni
- Visiting scientist from Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China to The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
| | - Lisa A Mielke
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Tracy L Putoczki
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
| | - Lorraine A O'Reilly
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
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11
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Chepngeno J, Takanashi S, Diaz A, Michael H, Paim FC, Rahe MC, Hayes JR, Baker C, Marthaler D, Saif LJ, Vlasova AN. Comparative Sequence Analysis of Historic and Current Porcine Rotavirus C Strains and Their Pathogenesis in 3-Day-Old and 3-Week-Old Piglets. Front Microbiol 2020; 11:780. [PMID: 32395116 PMCID: PMC7197332 DOI: 10.3389/fmicb.2020.00780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022] Open
Abstract
The increased prevalence of porcine group C rotavirus (PRVC) in suckling piglets and the emergence of new genetically distinct PRVC strains are concerning due to the associated significant economic losses they cause to the swine industry. We sequenced and analyzed two new PRVC strains, RV0104 (G3), and RV0143 (G6) and compared their pathogenesis with that of the historic strain Cowden (G1) in gnotobiotic (Gn) pigs. Near complete genome sequence analysis confirmed that these two strains were distinct from one another and the Cowden strain. VP1, VP2, VP6, NSP1-NSP3, and NSP5 genes were more similar between Cowden and RV0143, whereas VP3, VP7, and NSP4 shared higher nucleotide identity between Cowden and RV0104. Three-day-old and 3-week-old Gn piglets were inoculated with 105 FFU/piglet of Cowden, RV0104 or RV0143, or mock. All 3-day-old piglets developed severe diarrhea, anorexia, and lethargy, with mean PRVC fecal shedding titers peaking and numerically higher in RV0104 and RV0143 piglets on post infection day (PID) 2. Histopathological examination of the small intestine revealed that the 3-day-old Cowden and RV0104 inoculated piglets were mildly affected, while significant destruction of small intestinal villi was observed in the RV0143 inoculated piglets. Consistent with the highest degree of pathological changes in the small intestines, the RV0143 inoculated piglets had numerically higher levels of serum IL-17 and IFN-α cytokines and numerically lower PRVC IgA geometric mean antibody titers. Milder pathological changes and overall higher titers of PRVC IgA antibodies were observed in 3-week-old vs. 3-day-old piglets. Additionally, diarrhea was only observed in RV0104 and RV0143 (but not Cowden) inoculated 3-week-old piglets, while levels of serum IL-10 and PRVC IgA antibodies were higher in Cowden inoculated pigs, consistent with the lack of diarrhea. Thus, we confirmed that these current, genetically heterogeneous PRVC strains possess distinct pathobiological characteristics that may contribute to the increased prevalence of PRVC diarrhea in neonatal suckling piglets.
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Affiliation(s)
- Juliet Chepngeno
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Sayaka Takanashi
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States.,Department of Developmental Medical Sciences, The University of Tokyo, Tokyo, Japan
| | - Annika Diaz
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States.,Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH, United States
| | - Husheem Michael
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Francine C Paim
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Michael C Rahe
- Department of Veterinary Diagnostic and Production Animal Medicine, Iowa State University, Ames, IA, United States
| | - Jeffrey R Hayes
- Animal Disease Diagnostic Laboratory, The Ohio Department of Agriculture, Reynoldsburg, OH, United States
| | - Courtney Baker
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States.,Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH, United States
| | - Douglas Marthaler
- Kansas State Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States
| | - Linda J Saif
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Anastasia N Vlasova
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
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12
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Kumar S, Sunagar R, Gosselin EJ. Preclinical Efficacy of a Trivalent Human FcγRI-Targeted Adjuvant-Free Subunit Mucosal Vaccine against Pulmonary Pneumococcal Infection. Vaccines (Basel) 2020; 8:vaccines8020193. [PMID: 32340134 PMCID: PMC7349865 DOI: 10.3390/vaccines8020193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/03/2020] [Accepted: 04/17/2020] [Indexed: 12/25/2022] Open
Abstract
Lack of safe and effective mucosal adjuvants has severely hampered the development of mucosal subunit vaccines. In this regard, we have previously shown that immunogenicity of vaccine antigens can be improved by targeting the antigens to the antigen-presenting cells. Specifically, groups of mice immunized intranasally with a fusion protein (Bivalent-FP) containing a fragment of pneumococcal-surface-protein-A (PspA) as antigen and a single-chain bivalent antibody raised against the anti-human Fc-gamma-receptor-I (hFcγRI) elicited protective immunity to pulmonary Streptococcus pneumoniae infection. In order to further enhance the immunogenicity, an additional hFcγRI-binding moiety of the single chain antibody was incorporated. The modified vaccine (Trivalent-FP) induced significantly improved protection against lethal pulmonary S. pneumoniae challenge compared to Bivalent-FP. In addition, the modified vaccine exhibited over 85% protection with only two immunizations. Trivalent-FP also induced S. pneumoniae-specific systemic and mucosal antibodies. Moreover, Trivalent-FP also induced IL-17- and IL-22-producing CD4+ T cells. Furthermore, it was found that the hFcγRI facilitated uptake and presentation of Trivalent-FP. In addition, Trivalent-FP also induced IL-1α, MIP-1α, and TNF-α; modulated recruitment of dendritic cells and macrophages; and induced CD80/86 and MHC-II expression on antigen presenting cells.
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Affiliation(s)
- Sudeep Kumar
- Department of Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208, USA;
| | - Raju Sunagar
- Ella Foundation, Genome Valley, Hyderabad 500078, India;
| | - Edmund J. Gosselin
- Department of Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208, USA;
- Correspondence:
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13
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Jiang Y, Wang X, Dong C. Molecular mechanisms of T helper 17 cell differentiation: Emerging roles for transcription cofactors. Adv Immunol 2019; 144:121-153. [PMID: 31699215 DOI: 10.1016/bs.ai.2019.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
T helper 17 (Th17) cells, characterized by secretion of IL-17 and IL-17F, are a specialized CD4+ effector T cell lineage that not only facilitates host defense against pathogen infection and maintenance of mucosal barrier, but also potently induces tissue inflammation and autoimmune diseases. Since its discovery in 2005, the developmental program of Th17 cells has been characterized, which involves a number of key cytokines, transcription factors and multiple layers of epigenetic modifications. However, how these mechanisms integrate into the complex regulatory network in Th17 cells has not been well defined. Emerging evidences have revealed essential roles of cofactors in controlling chromosome accessibilities and activities of Th17-specific transcription factors. Moreover, cofactors also act as critical signaling integrators to coordinate multiple signaling pathways and transcriptional programs. Deficiency or dysregulation of these cofactors results in defects in Th17 responses and induction of associated autoimmune diseases. Our lab has recently reported several important cofactors in Th17 cells. Here we summarize our findings regarding this new scenario of developmental regulation of Th17 cells. These findings may benefit the development of innovative strategies to treat autoimmune diseases.
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Affiliation(s)
- Yu Jiang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Xiaohu Wang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing, China.
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14
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Shindo R, Ohmuraya M, Komazawa-Sakon S, Miyake S, Deguchi Y, Yamazaki S, Nishina T, Yoshimoto T, Kakuta S, Koike M, Uchiyama Y, Konishi H, Kiyama H, Mikami T, Moriwaki K, Araki K, Nakano H. Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis. iScience 2019; 15:536-551. [PMID: 31132747 PMCID: PMC6538961 DOI: 10.1016/j.isci.2019.05.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/12/2019] [Accepted: 05/09/2019] [Indexed: 12/15/2022] Open
Abstract
A short form of cellular FLICE-inhibitory protein encoded by CFLARs promotes necroptosis. Although necroptosis is involved in various pathological conditions, the detailed mechanisms are not fully understood. Here we generated transgenic mice wherein CFLARs was integrated onto the X chromosome. All male CFLARs Tg mice died perinatally due to severe ileitis. Although necroptosis was observed in various tissues of CFLARs Tg mice, large numbers of intestinal epithelial cells (IECs) died by apoptosis. Deletion of Ripk3 or Mlkl, essential genes of necroptosis, prevented both necroptosis and apoptosis, and rescued lethality of CFLARs Tg mice. Type 3 innate lymphoid cells (ILC3s) were activated and recruited to the small intestine along with upregulation of interleukin-22 (Il22) in CFLARs Tg mice. Deletion of ILC3s or Il22 rescued lethality of CFLARs Tg mice by preventing apoptosis, but not necroptosis of IECs. Together, necroptosis-dependent activation of ILC3s induces lethal ileitis in an IL-22-dependent manner.
CFLARs Tg mice develop severe ileitis in utero Intestinal epithelial cells die by apoptosis and necroptosis in CFLARs Tg mice Blockade of necroptosis rescues lethality of CFLARs Tg mice Necroptosis activates type 3 innate lymphoid cells, resulting in severe ileitis
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Affiliation(s)
- Ryodai Shindo
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Masaki Ohmuraya
- Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Sachiko Komazawa-Sakon
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Sanae Miyake
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Yutaka Deguchi
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Soh Yamazaki
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Takashi Nishina
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Takayuki Yoshimoto
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku-ku, Tokyo 160-8402, Japan
| | - Soichiro Kakuta
- Department of Cellular Molecular Neuropathology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Masato Koike
- Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yasuo Uchiyama
- Department of Cellular Molecular Neuropathology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Hiroyuki Konishi
- Department of Functional Anatomy and Neuroscience, Graduate School of Medicine, Nagoya University, 65 Tsurumaicho, Showa-ku, Nagoya 466-8560, Japan
| | - Hiroshi Kiyama
- Department of Functional Anatomy and Neuroscience, Graduate School of Medicine, Nagoya University, 65 Tsurumaicho, Showa-ku, Nagoya 466-8560, Japan
| | - Tetuo Mikami
- Department of Pathology, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan
| | - Kenta Moriwaki
- Department of Cell Biology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kimi Araki
- Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
| | - Hiroyasu Nakano
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan; Host Defense Research Center, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan.
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15
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Mendes V, Galvão I, Vieira AT. Mechanisms by Which the Gut Microbiota Influences Cytokine Production and Modulates Host Inflammatory Responses. J Interferon Cytokine Res 2019; 39:393-409. [PMID: 31013453 DOI: 10.1089/jir.2019.0011] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract encounters a wide variety of microorganisms, including beneficial symbionts, pathobionts, and pathogens. Recent evidence has shown that the gut microbiota, directly or indirectly through its components, such as metabolites, actively participates in the host inflammatory response by cytokine-microbiota or microbiota-cytokine modulation interactions, both in the gut and systemically. Therefore, further elucidation of host cytokine molecular pathways and microbiota components will provide a novel and promising therapeutic approach to control or prevent inflammatory disease and to maintain host homeostasis. The purpose of this review is to summarize well-established scientific findings and provide an updated overview regarding the direct and indirect mechanisms by which the gut microbiota can influence the inflammatory response by modulating the host's cytokine pathways that are mostly involved, but not exclusively so, with gut homeostasis. In addition, we will highlight recent results from our group, which suggest that the microbiota promotes cytokine release from inflammatory cells though activation of microbial metabolite sensor receptors that are more highly expressed on inflammatory and intestinal epithelial cells.
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Affiliation(s)
- Viviani Mendes
- 1 Laboratory of Microbiota and Immunomodulation, Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,2 Department of General Biology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Izabela Galvão
- 3 Department of Cellular Biology ICB, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Angelica Thomaz Vieira
- 1 Laboratory of Microbiota and Immunomodulation, Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,2 Department of General Biology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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16
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Nagasawa M, Spits H, Ros XR. Innate Lymphoid Cells (ILCs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis. Cold Spring Harb Perspect Biol 2018; 10:cshperspect.a030304. [PMID: 29229782 DOI: 10.1101/cshperspect.a030304] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Innate lymphoid cells (ILCs) have emerged as an expanding family of effector cells particularly enriched in the mucosal barriers. ILCs are promptly activated by stress signals and multiple epithelial- and myeloid-cell-derived cytokines. In response, ILCs rapidly secrete effector cytokines, which allow them to survey and maintain the mucosal integrity. Uncontrolled action of ILCs might contribute to tissue damage, chronic inflammation, metabolic diseases, autoimmunity, and cancer. Here we discuss the recent advances in our understanding of the cytokine network that modulate ILC immune responses: stimulating cytokines, signature cytokines secreted by ILC subsets, autocrine cytokines, and cytokines that induce cell plasticity.
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Affiliation(s)
- Maho Nagasawa
- Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, 1105 BA Amsterdam, Netherlands
| | - Hergen Spits
- Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, 1105 BA Amsterdam, Netherlands
| | - Xavier Romero Ros
- Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, 1105 BA Amsterdam, Netherlands
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17
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Al Obeed OA, Vaali-Mohamed MA, Alkhayal KA, Bin Traiki TA, Zubaidi AM, Arafah M, Harris RA, Khan Z, Abdulla MH. IL-17 and colorectal cancer risk in the Middle East: gene polymorphisms and expression. Cancer Manag Res 2018; 10:2653-2661. [PMID: 30233234 PMCID: PMC6130533 DOI: 10.2147/cmar.s161248] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background IL-17 expressed by Th17 cells play a crucial role in tissue inflammation by induction of proinflammatory and neutrophil mobilizing cytokines, and IL-17 polymorphisms are associated with colorectal cancer (CRC). Objective We investigated the expression of IL-17 and the association of IL-17 gene polymorphisms with CRC susceptibility in a Middle East population. Materials and methods The study included 117 diagnosed CRC patients and 100 age- and gender-matched healthy controls. IL-17A rs2275913 (G197A) and IL-17F rs763780 (T7488C) single nucleotide polymorphisms, mRNA, and protein levels of IL-17A were assessed. Results We observed significant association between rs2275913 in IL-17A and susceptibility to CRC (p = 0.016228). The AG and AA genotypes conferred 2-fold and 2.8-fold, respectively, higher risk of developing CRC compared with individuals having GG genotype. Stratification of the data based on gender and age revealed very strong association of CRC with IL17A rs2275913 only in males and “AG” genotype in patients ≤57 years of age at the time of disease diagnosis. The rs763780 in IL-17F was not linked with CRCs in our cohort. Furthermore, IL-17A mRNA expression in CRCs was significantly elevated compared to adjacent normal tissues, particularly in early stages of disease (p = 0.0005). Strong immunoreactivity to IL-17A protein was observed in 70% of early stage relative to 30% of late-stage tumors. Conclusion The IL-17A G197A variant may be utilized as a genetic screening marker in assessing CRC risk, and its expression can be used as a biomarker for early detection of CRC in the Saudi population.
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Affiliation(s)
- Omar A Al Obeed
- Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
| | - Mansoor-Ali Vaali-Mohamed
- Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
| | - Khayal A Alkhayal
- Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
| | - Thamer A Bin Traiki
- Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
| | - Ahmad M Zubaidi
- Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
| | - Maha Arafah
- Department of Pathology, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Robert A Harris
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Zahid Khan
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia,
| | - Maha-Hamadien Abdulla
- Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
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18
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Swafford D, Shanmugam A, Ranganathan P, Hussein MS, Koni PA, Prasad PD, Thangaraju M, Manicassamy S. Canonical Wnt Signaling in CD11c + APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon. THE JOURNAL OF IMMUNOLOGY 2018; 200:3259-3268. [PMID: 29602775 DOI: 10.4049/jimmunol.1701086] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 03/08/2018] [Indexed: 12/14/2022]
Abstract
Aberrant Wnt/β-catenin signaling occurs in several inflammatory diseases, including inflammatory bowel disease and inflammatory bowel disease-associated colon carcinogenesis. However, its role in shaping mucosal immune responses to commensals in the gut remains unknown. In this study, we investigated the importance of canonical Wnt signaling in CD11c+ APCs in controlling intestinal inflammation. Using a mouse model of ulcerative colitis, we demonstrated that canonical Wnt signaling in intestinal CD11c+ APCs controls intestinal inflammation by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt coreceptors, low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) in CD11c+ APCs in LRP5/6ΔCD11c mice, resulted in enhanced intestinal inflammation with increased histopathological severity of colonic tissue. This was due to microbiota-dependent increased production of proinflammatory cytokines and decreased expression of immune-regulatory factors such as IL-10, retinoic acid, and IDO. Mechanistically, loss of LRP5/6-mediated signaling in CD11c+ APCs resulted in altered microflora and T cell homeostasis. Furthermore, our study demonstrates that conditional activation of β-catenin in CD11c+ APCs in LRP5/6ΔCD11c mice resulted in reduced intestinal inflammation with decreased histopathological severity of colonic tissue. These results reveal a mechanism by which intestinal APCs control intestinal inflammation and immune homeostasis via the canonical Wnt-signaling pathway.
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Affiliation(s)
- Daniel Swafford
- Georgia Cancer Center, Augusta University, Augusta, GA 30912
| | | | | | | | - Pandelakis A Koni
- Georgia Cancer Center, Augusta University, Augusta, GA 30912.,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912; and.,Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912
| | - Puttur D Prasad
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912; and
| | - Muthusamy Thangaraju
- Georgia Cancer Center, Augusta University, Augusta, GA 30912.,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912; and
| | - Santhakumar Manicassamy
- Georgia Cancer Center, Augusta University, Augusta, GA 30912; .,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912; and.,Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912
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19
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Li P, Xu Z, Sun X, Yin Y, Fan Y, Zhao J, Mao X, Huang J, Yang F, Zhu L. Transcript profiling of the immunological interactions between Actinobacillus pleuropneumoniae serotype 7 and the host by dual RNA-seq. BMC Microbiol 2017; 17:193. [PMID: 28899359 PMCID: PMC5596872 DOI: 10.1186/s12866-017-1105-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 09/05/2017] [Indexed: 02/08/2023] Open
Abstract
Background The complexity of the pathogenic mechanism underlying the host immune response to Actinobacillus pleuropneumonia (App) makes the use of preventive measures difficult, and a more global view of the host-pathogen interactions and new insights into this process are urgently needed to reveal the pathogenic and immune mechanisms underlying App infection. Here, we infected specific pathogen-free Mus musculus with App serotype 7 by intranasal inoculation to construct an acute hemorrhagic pneumonia infection model and isolated the infected lungs for analysis of the interactions by dual RNA-seq. Results Four cDNA libraries were constructed, and 2428 differentially expressed genes (DEGs) of the host and 333 DEGs of App were detected. The host DEGs were mainly enriched in inflammatory signaling pathways, such as the TLR, NLR, RLR, BCR and TCR signaling pathways, resulting in large-scale cytokine up-regulation and thereby yielding a cytokine cascade for anti-infection and lung damage. The majority of the up-regulated cytokines are involved in the IL-23/IL-17 cytokine-regulated network, which is crucial for host defense against bacterial infection. The DEGs of App were mainly related to the transport and metabolism of energy and materials. Most of these genes are metabolic genes involved in anaerobic metabolism and important for challenging the host and adapting to the anaerobic stress conditions observed in acute hemorrhagic pneumonia. Some of these genes, such as adhE, dmsA, and aspA, might be potential virulence genes. In addition, the up-regulation of genes associated with peptidoglycan and urease synthesis and the restriction of major virulence genes might be immune evasion strategies of App. The regulation of metabolic genes and major virulence genes indicate that the dominant antigens might differ during the infection process and that vaccines based on these antigens might allow establishment of a precise and targeted immune response during the early phase of infection. Conclusion Through an analysis of transcriptional data by dual RNA-seq, our study presents a novel global view of the interactions of App with its host and provides a basis for further study. Electronic supplementary material The online version of this article (10.1186/s12866-017-1105-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ping Li
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Zhiwen Xu
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Xiangang Sun
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China
| | - Yue Yin
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Yi Fan
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Jun Zhao
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Xiyu Mao
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Jianbo Huang
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Fan Yang
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Ling Zhu
- College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, Weenjiang District, Chengdu, Sichuan, China. .,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China.
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20
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Che KF, Kaarteenaho R, Lappi-Blanco E, Levänen B, Sun J, Wheelock Å, Palmberg L, Sköld CM, Lindén A. Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines. Mol Med 2017; 23:247-257. [PMID: 28853490 DOI: 10.2119/molmed.2016.00064] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 08/21/2017] [Indexed: 12/22/2022] Open
Abstract
Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro, and exploring the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airway structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines.
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Affiliation(s)
- Karlhans Fru Che
- Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77 Stockholm, Sweden
| | - Riitta Kaarteenaho
- Unit of Medicine and Clinical Research, Pulmonary Division, University of Eastern Finland and Center of Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Elisa Lappi-Blanco
- Department of Pathology, Center for Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
| | - Bettina Levänen
- Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77 Stockholm, Sweden
| | - Jitong Sun
- Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77 Stockholm, Sweden
| | - Åsa Wheelock
- Respiratory Medicine Unit. Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm
| | - Lena Palmberg
- Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77 Stockholm, Sweden
| | - C Magnus Sköld
- Respiratory Medicine Unit. Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm.,Lung Allergy Clinic, Karolinska University Hospital Solna, Stockholm, SE-171 76 Stockholm, Sweden
| | - Anders Lindén
- Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77 Stockholm, Sweden.,Lung Allergy Clinic, Karolinska University Hospital Solna, Stockholm, SE-171 76 Stockholm, Sweden
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21
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Xue M, Zhao J, Ying L, Fu F, Li L, Ma Y, Shi H, Zhang J, Feng L, Liu P. IL-22 suppresses the infection of porcine enteric coronaviruses and rotavirus by activating STAT3 signal pathway. Antiviral Res 2017; 142:68-75. [PMID: 28322925 PMCID: PMC7113769 DOI: 10.1016/j.antiviral.2017.03.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/09/2017] [Accepted: 03/13/2017] [Indexed: 12/19/2022]
Abstract
Interleukin-22 (IL-22), a member of the IL-10 superfamily, plays essential roles in fighting against mucosal microbial infection and maintaining mucosal barrier integrity within the intestine. However, little knowledge exists on the ability of porcine IL-22 (pIL-22) to fight against viral infection in the gut. In this study, we found that recombinant mature pIL-22 (mpIL-22) inhibited the infection of multiple diarrhea viruses, including alpha coronavirus, porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine rotavirus (PoRV), in the intestinal porcine epithelial cell line J2 (IPEC-J2) cells. mpIL-22 up-regulated the expression of the antimicrobial peptide beta-defensin (BD-2), cytokine IL-18 and IFN-λ. Furthermore, we found that mpIL-22 induced phosphorylation of STAT3 on Ser727 and Tyr705 in IPEC-J2 cells. Inhibition of STAT3 phosphorylation by S3I-201 abrogated the antiviral ability of mpIL-22 and the mpIL-22-induced expression of BD-2, IL-18, and IFN-λ. Together, mpIL-22 inhibited the infection of PoRV and enteric coronaviruses, and up-regulated the expression of antimicrobial genes in IPEC-J2, which were mediated by the activation of the STAT3 signal pathway. The significant antiviral activity of IL-22 to curtail multiple enteric diarrhea viruses in vitro suggests that pIL-22 could be a novel therapeutic against devastating viral diarrhea in piglets.
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Affiliation(s)
- Mei Xue
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Jing Zhao
- College of Agriculture and Animal Husbandry, Qinghai University, Xining, 810003, China
| | - Lan Ying
- College of Agriculture and Animal Husbandry, Qinghai University, Xining, 810003, China
| | - Fang Fu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Lin Li
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Yanlong Ma
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Hongyan Shi
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Jiaoer Zhang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Li Feng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China.
| | - Pinghuang Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China.
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22
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Toshkov IA, Gleiberman AS, Mett VL, Hutson AD, Singh AK, Gudkov AV, Burdelya LG. Mitigation of Radiation-Induced Epithelial Damage by the TLR5 Agonist Entolimod in a Mouse Model of Fractionated Head and Neck Irradiation. Radiat Res 2017; 187:570-580. [PMID: 28323577 PMCID: PMC5541767 DOI: 10.1667/rr14514.1] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Radiation treatment of head and neck cancer frequently causes severe collateral damage to normal tissues including mouth mucosa, salivary glands and skin. This toxicity limits the radiation dose that can be delivered and affects the patient's quality of life. Previous studies in mice and nonhuman primates showed that entolimod, a toll-like receptor 5 (TLR5) agonist derived from bacterial flagellin, effectively reduced radiation damage to hematopoietic and gastrointestinal tissues in both total-body and local irradiation scenarios, with no protection of tumors. Here, using a mouse model, we analyzed the efficacy of entolimod administered before or after irradiation in reducing damage to normal tissues. Animals received local fractionated radiation to the head and neck area, thus modeling radiotherapy of head and neck cancer. Tissue damage was evaluated through histomorphological examination of samples collected at different time points up to four weeks, mice were exposed locally to five daily fractions of 5, 6 or 7 Gy. A semiquantitative scoring system was used to assess the severity of observed pathomorphological changes. In this model, radiation damage was most severe in the lips, tongue and skin, moderate in the upper esophagus and minor in salivary glands. The kinetics of injury appearance and recovery of normal morphology varied among tissues, with maximal damage to the tongue, esophagus and salivary glands developing at earlier times (days 8-11 postirradiation) relative to that of lip and skin mucosa (days 11-15 postirradiation). While both tested regimens of entolimod significantly reduced the extent of radiation damage and accelerated restoration of normal structure in all tissues analyzed, administration of entolimod 1 h after each irradiation was more effective than treatment 30 min before irradiation. These results support the potential clinical use of entolimod as an adjuvant for improving the therapeutic index of head and neck cancer radiotherapy by reducing the radiation toxicity in normal tissues.
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Affiliation(s)
| | | | | | - Alan D. Hutson
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York
| | - Anurag K. Singh
- Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, New York
| | - Andrei V. Gudkov
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York
- Cleveland BioLabs, Inc., Buffalo, New York
| | - Lyudmila G. Burdelya
- Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York
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23
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Marquet S, Conte I, Poudiougou B, Argiro L, Dessein H, Couturier C, Burté F, Oumar AA, Brown BJ, Traore A, Afolabi NK, Barry A, Omokhodion S, Shokunbi WA, Sodeinde O, Doumbo O, Fernandez-Reyes D, Dessein AJ. A Functional IL22 Polymorphism (rs2227473) Is Associated with Predisposition to Childhood Cerebral Malaria. Sci Rep 2017; 7:41636. [PMID: 28139719 PMCID: PMC5282577 DOI: 10.1038/srep41636] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023] Open
Abstract
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection. This encephalopathy is characterized by coma and is thought to result from mechanical microvessel obstruction and an excessive activation of immune cells leading to pathological inflammation and blood-brain barrier alterations. IL-22 contributes to both chronic inflammatory and infectious diseases, and may have protective or pathogenic effects, depending on the tissue and disease state. We evaluated whether polymorphisms (n = 46) of IL22 and IL22RA2 were associated with CM in children from Nigeria and Mali. Two SNPs of IL22, rs1012356 (P = 0.016, OR = 2.12) and rs2227476 (P = 0.007, OR = 2.08) were independently associated with CM in a sample of 115 Nigerian children with CM and 160 controls. The association with rs2227476 (P = 0.01) was replicated in 240 nuclear families with one affected child from Mali. SNP rs2227473, in linkage disequilibrium with rs2227476, was also associated with CM in the combined cohort for these two populations, (P = 0.004, OR = 1.55). SNP rs2227473 is located within a putative binding site for the aryl hydrocarbon receptor, a master regulator of IL-22 production. Individuals carrying the aggravating T allele of rs2227473 produced significantly more IL-22 than those without this allele. Overall, these findings suggest that IL-22 is involved in the pathogenesis of CM.
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Affiliation(s)
- Sandrine Marquet
- Aix-Marseille University, INSERM, GIMP, Labex ParaFrap, Marseille, France
| | - Ianina Conte
- Department of Computer Science, Faculty of Engineering Sciences, University College London, Gower Street, London, WCE2 6BT, United Kingdom
| | - Belco Poudiougou
- Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, USTTB, BP 1805, Bamako, Mali
| | - Laurent Argiro
- Aix-Marseille University, INSERM, GIMP, Labex ParaFrap, Marseille, France
| | - Hélia Dessein
- Aix-Marseille University, INSERM, GIMP, Labex ParaFrap, Marseille, France
| | - Charlène Couturier
- Aix-Marseille University, INSERM, GIMP, Labex ParaFrap, Marseille, France
| | - Florence Burté
- Department of Computer Science, Faculty of Engineering Sciences, University College London, Gower Street, London, WCE2 6BT, United Kingdom
| | - Aboubacar A. Oumar
- Centre des Oeuvres Universitaires, University of Bamako, BP 1805, Bamako, Mali
| | - Biobele J. Brown
- Department of Pediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Department of Hematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
| | - Abdoualye Traore
- Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, USTTB, BP 1805, Bamako, Mali
| | - Nathaniel K. Afolabi
- Department of Pediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
| | | | - Samuel Omokhodion
- Department of Pediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
| | - Wuraola A. Shokunbi
- Department of Hematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
| | - Olugbemiro Sodeinde
- Department of Computer Science, Faculty of Engineering Sciences, University College London, Gower Street, London, WCE2 6BT, United Kingdom
- Department of Pediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Department of Hematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
| | - Ogobara Doumbo
- Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, USTTB, BP 1805, Bamako, Mali
| | - Delmiro Fernandez-Reyes
- Department of Computer Science, Faculty of Engineering Sciences, University College London, Gower Street, London, WCE2 6BT, United Kingdom
- Department of Pediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Department of Hematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
- Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
| | - Alain J. Dessein
- Aix-Marseille University, INSERM, GIMP, Labex ParaFrap, Marseille, France
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24
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Manoharan I, Suryawanshi A, Hong Y, Ranganathan P, Shanmugam A, Ahmad S, Swafford D, Manicassamy B, Ramesh G, Koni PA, Thangaraju M, Manicassamy S. Homeostatic PPARα Signaling Limits Inflammatory Responses to Commensal Microbiota in the Intestine. THE JOURNAL OF IMMUNOLOGY 2016; 196:4739-49. [PMID: 27183583 DOI: 10.4049/jimmunol.1501489] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 03/25/2016] [Indexed: 12/28/2022]
Abstract
Dietary lipids and their metabolites activate members of the peroxisome proliferative-activated receptor (PPAR) family of transcription factors and are critical for colonic health. The PPARα isoform plays a vital role in regulating inflammation in various disease settings, but its role in intestinal inflammation, commensal homeostasis, and mucosal immunity in the gut are unclear. In this study, we demonstrate that the PPARα pathway in innate immune cells orchestrates gut mucosal immunity and commensal homeostasis by regulating the expression of IL-22 and the antimicrobial peptides RegIIIβ, RegIIIγ, and calprotectin. Additionally, the PPARα pathway is critical for imparting regulatory phenotype in intestinal macrophages. PPARα deficiency in mice led to commensal dysbiosis in the gut, resulting in a microbiota-dependent increase in the expression of inflammatory cytokines and enhanced susceptibility to intestinal inflammation. Pharmacological activation of this pathway decreased the expression of inflammatory cytokines and ameliorated colonic inflammation. Taken together, these findings identify a new important innate immune function for the PPARα signaling pathway in regulating intestinal inflammation, mucosal immunity, and commensal homeostasis. Thus, the manipulation of the PPARα pathway could provide novel opportunities for enhancing mucosal immunity and treating intestinal inflammation.
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Affiliation(s)
| | | | - Yuan Hong
- Cancer Center, Augusta University, Augusta, GA 30912
| | | | | | - Shamim Ahmad
- Cancer Center, Augusta University, Augusta, GA 30912
| | | | | | - Ganesan Ramesh
- Vascular Biology Center, Augusta University, Augusta, GA 30912
| | - Pandelakis A Koni
- Cancer Center, Augusta University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912; and
| | - Muthusamy Thangaraju
- Cancer Center, Augusta University, Augusta, GA 30912; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912
| | - Santhakumar Manicassamy
- Cancer Center, Augusta University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912; and Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912
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Sivanesan D, Beauchamp C, Quinou C, Lee J, Lesage S, Chemtob S, Rioux JD, Michnick SW. IL23R (Interleukin 23 Receptor) Variants Protective against Inflammatory Bowel Diseases (IBD) Display Loss of Function due to Impaired Protein Stability and Intracellular Trafficking. J Biol Chem 2016; 291:8673-85. [PMID: 26887945 DOI: 10.1074/jbc.m116.715870] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Indexed: 01/19/2023] Open
Abstract
Genome-wide association studies as well as murine models have shown that the interleukin 23 receptor (IL23R) pathway plays a pivotal role in chronic inflammatory diseases such as Crohn disease (CD), ulcerative colitis, psoriasis, and type 1 diabetes. Genome-wide association studies and targeted re-sequencing studies have revealed the presence of multiple potentially causal variants of the IL23R. Specifically the G149R, V362I, and R381Q IL23Rα chain variants are linked to protection against the development of Crohn disease and ulcerative colitis in humans. Moreover, the exact mechanism of action of these receptor variants has not been elucidated. We show that all three of these IL23Rα variants cause a reduction in IL23 receptor activation-mediated phosphorylation of the signal-transducing activator of transcription 3 (STAT3) and phosphorylation of signal transducing activator of transcription 4 (STAT4). The reduction in signaling is due to lower levels of cell surface receptor expression. For G149R, the receptor retention in the endoplasmic reticulum is due to an impairment of receptor maturation, whereas the R381Q and V362I variants have reduced protein stability. Finally, we demonstrate that the endogenous expression of IL23Rα protein from V362I and R381Q variants in human lymphoblastoid cell lines exhibited lower expression levels relative to susceptibility alleles. Our results suggest a convergent cause of IL23Rα variant protection against chronic inflammatory disease.
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Affiliation(s)
- Durga Sivanesan
- From the Department of Biochemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada, University of Ottawa, Department of Biochemistry, Microbiology, and Immunology, Ottawa, Ontario K1H 8M5, Canada
| | - Claudine Beauchamp
- University of Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada
| | - Christiane Quinou
- CHU Sainte-Justine, Research Centre, Montreal, Quebec H3T 1C5, Canada, and
| | - Jonathan Lee
- University of Ottawa, Department of Biochemistry, Microbiology, and Immunology, Ottawa, Ontario K1H 8M5, Canada
| | - Sylvie Lesage
- Centre of Recherche Hospital Maisonneuve-Rosemont, Department of Microbiology, Infection, and Immunology, University of Montreal, Montreal, Quebec H1T 2M4, Canada
| | - Sylvain Chemtob
- CHU Sainte-Justine, Research Centre, Montreal, Quebec H3T 1C5, Canada, and
| | - John D Rioux
- University of Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada
| | - Stephen W Michnick
- From the Department of Biochemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada,
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Isaza-Guzmán DM, Cardona-Vélez N, Gaviria-Correa DE, Martínez-Pabón MC, Castaño-Granada MC, Tobón-Arroyave SI. Association study between salivary levels of interferon (IFN)-gamma, interleukin (IL)-17, IL-21, and IL-22 with chronic periodontitis. Arch Oral Biol 2015; 60:91-9. [PMID: 25285903 DOI: 10.1016/j.archoralbio.2014.09.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 09/14/2014] [Accepted: 09/16/2014] [Indexed: 01/21/2023]
Abstract
OBJECTIVE To investigate if the salivary levels of IL-17, IL-21, IL-22, and its ratio regarding salivary IFN-γ may be linked with the periodontal clinical status. DESIGN One hundred and five chronic periodontitis (CP) subjects and 44 healthy controls (HC) were recruited. Periodontal status was assessed based on full-mouth clinical periodontal measurements. Cytokine salivary levels were analyzed by ELISA. The association between the analytes with CP was analyzed using a binary logistic regression model. RESULTS A statistically significant increase in salivary levels of IFN-γ and IFN-γ/IL-22 ratio in CP group could be detected, but there was no significant domination of any Th17 cytokine that could be of predictive value for health/disease status. Univariate and binary logistic regression analyses revealed a strong and independent association of IFN-γ salivary levels and IFN-γ/IL-22 ratio with disease status. An interaction effect of ageing on IFN-γ levels also could be noted. CONCLUSION While salivary levels of IFN-γ and IFN-γ/IL-22 ratio may act as strong/independent indicators of the amount and extent of periodontal breakdown, the low detection frequency of Th17 cytokines in saliva samples make these determinations useless for the detection of disease presence and/or its severity.
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Affiliation(s)
- D M Isaza-Guzmán
- POPCAD Research Group, Laboratory of Immunodetection and Bioanalysis, Faculty of Dentistry, University of Antioquia, Medellín, Colombia
| | - N Cardona-Vélez
- POPCAD Research Group, Laboratory of Immunodetection and Bioanalysis, Faculty of Dentistry, University of Antioquia, Medellín, Colombia
| | - D E Gaviria-Correa
- POPCAD Research Group, Laboratory of Immunodetection and Bioanalysis, Faculty of Dentistry, University of Antioquia, Medellín, Colombia
| | - M C Martínez-Pabón
- POPCAD Research Group, Laboratory of Immunodetection and Bioanalysis, Faculty of Dentistry, University of Antioquia, Medellín, Colombia
| | - M C Castaño-Granada
- POPCAD Research Group, Laboratory of Immunodetection and Bioanalysis, Faculty of Dentistry, University of Antioquia, Medellín, Colombia
| | - S I Tobón-Arroyave
- POPCAD Research Group, Laboratory of Immunodetection and Bioanalysis, Faculty of Dentistry, University of Antioquia, Medellín, Colombia.
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Hajishengallis G, Russell MW. Innate Humoral Defense Factors. Mucosal Immunol 2015. [PMCID: PMC7149745 DOI: 10.1016/b978-0-12-415847-4.00015-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although innate immunity came into the research spotlight in the late 1990s when its instructive role in the adaptive immune response was recognized, innate humoral defense factors have a much older history. The exocrine secretions of the body contain a plethora of distinct soluble factors (lysozyme, lactoferrin, peroxidases, proline-rich proteins, histatins, etc.) that protect the body from mucosal microbial pathogens. More recent studies have established that the humoral arm of innate immunity contains a heterogeneous group of pattern-recognition molecules (e.g., pentraxins, collectins, and ficolins), which perform diverse host-defense functions, such as agglutination and neutralization, opsonization, control of inflammation, and complement activation and regulation. These pattern-recognition molecules, which act as functional predecessors of antibodies (“ante-antibodies”), and the classic soluble innate defense factors form an integrated system with complementary specificity, action, and tissue distribution, and they are the subject of this chapter.
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Xu H, Wang X, Veazey RS. Simian Immunodeficiency Virus Infection and Mucosal Immunity. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00076-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Li LJ, Gong C, Zhao MH, Feng BS. Role of interleukin-22 in inflammatory bowel disease. World J Gastroenterol 2014; 20:18177-88. [PMID: 25561785 PMCID: PMC4277955 DOI: 10.3748/wjg.v20.i48.18177] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 06/21/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract, leading to further inflammation. Interleukin (IL)-22 is a member of the IL-10 family of cytokines that was recently discovered to be mainly produced by both adaptive and innate immune cells. Several cytokines and many of the transcriptional factors and T regulatory cells are known to regulate IL-22 expression through activation of signal transducer and activator of transcription 3 signaling cascades. This cytokine induces antimicrobial molecules and proliferative and antiapoptotic pathways, which help prevent tissue damage and aid in its repair. All of these processes play a beneficial role in IBD by enhancing intestinal barrier integrity and epithelial innate immunity. In this review, we discuss recent progress in the involvement of IL-22 in the pathogenesis of IBD, as well as its therapeutic potential.
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Li JR, Zhou WX, Huang KW, Jin Y, Gao JM. Interleukin-22 exacerbates airway inflammation induced by short-term exposure to cigarette smoke in mice. Acta Pharmacol Sin 2014; 35:1393-401. [PMID: 25345745 PMCID: PMC4220081 DOI: 10.1038/aps.2014.91] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 07/31/2014] [Indexed: 12/11/2022]
Abstract
AIM Interleukin-22 (IL-22) exhibits both proinflammatory and anti-inflammatory properties in various biological processes. In this study we explored the effects of exogenous recombinant IL-22 (rIL-22) on cigarette smoke (CS)-induced airway inflammation in mice. METHODS Male C57BL/6 mice were divided into groups: (1) CS group exposed to tobacco smoke for 3 consecutive days, (2) rIL-22 group received rIL-22 (100 mg/kg, ip), and (3) CS plus rIL-22 group, received rIL-22 (100 mg/kg, ip) before the CS exposure. The airway resistance (Rn), lung morphology, inflammatory cells in the airways, and inflammatory cytokines and CXCR3 ligands in both bronchoalveolar lavage (BAL) fluids and lung tissues were analyzed. RESULTS CS alone significantly elevated IL-22 level in the BAL fluid. Both CS and rIL-22 significantly augmented airway resistance, an influx of inflammatory cells into the airways and lung parenchyma, and significantly elevated levels of pro-inflammatory cytokines (TGFβ1 and IL-17A) and CXCR3 chemokines (particularly CXCL10) at the mRNA and/or protein levels. Furthermore, the effects of rIL-22 on airway resistance and inflammation were synergistic with those of CS, as demonstrated by a further increased Rn value, infiltration of greater numbers of inflammatory cells into the lung, higher levels of inflammatory cytokines and chemokines, and more severe pathological changes in CS plus rIL-22 group as compared to those in CS group. CONCLUSION Exogenous rIL-22 exacerbates the airway inflammatory responses to CS exposure in part by inducing expression of several proinflammatory cytokines and CXCR3 ligands.
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Affiliation(s)
- Jiu-rong Li
- Department of Respiratory Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Wei-xun Zhou
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Ke-wu Huang
- Division of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yang Jin
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jin-ming Gao
- Department of Respiratory Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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Wu RQ, Zhang DF, Tu E, Chen QM, Chen W. The mucosal immune system in the oral cavity-an orchestra of T cell diversity. Int J Oral Sci 2014; 6:125-32. [PMID: 25105816 PMCID: PMC4170154 DOI: 10.1038/ijos.2014.48] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2014] [Indexed: 02/05/2023] Open
Abstract
The mucosal immune system defends against a vast array of pathogens, yet it exhibits limited responses to commensal microorganisms under healthy conditions. The oral-pharyngeal cavity, the gateway for both the gastrointestinal and respiratory tracts, is composed of complex anatomical structures and is constantly challenged by antigens from air and food. The mucosal immune system of the oral-pharyngeal cavity must prevent pathogen entry while maintaining immune homeostasis, which is achieved via a range of mechanisms that are similar or different to those utilized by the gastrointestinal immune system. In this review, we summarize the features of the mucosal immune system, focusing on T cell subsets and their functions. We also discuss our current understanding of the oral-pharyngeal mucosal immune system.
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Affiliation(s)
- Rui-Qing Wu
- 1] Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA [2] State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dun-Fang Zhang
- 1] Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA [2] State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Eric Tu
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA
| | - Qian-Ming Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - WanJun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA
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Identification of epicatechin as one of the key bioactive constituents of polyphenol-enriched extracts that demonstrate an anti-allergic effect in a murine model of food allergy. Br J Nutr 2014; 112:358-68. [DOI: 10.1017/s0007114514000877] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Polyphenols are naturally derived bioactive compounds with numerous reported health benefits. We have previously reported on the beneficial effect of a polyphenol-enriched apple extract in a murine model of food allergy. The objectives of the present study were to elucidate the class of bioactive polyphenols that exhibit a beneficial anti-allergic effect and to assess whether the protective effect matches the in vivo bioavailable metabolite concentrations. Female BALB/c mice were sensitised to ovalbumin (OVA) following the protocol of a well-established murine model of food allergy. They were fed diets containing polyphenol-enriched extracts or purified epicatechin for 8 d after the last sensitisation. The sensitised mice were orally challenged with OVA after the intervention. The allergy symptoms, in addition to allergen-specific serum Ig concentrations and gene expression profiles in the intestine, of the control and treated mice were compared. Plasma samples were collected to compare the concentrations of bioavailable epicatechin metabolites in the treatment groups. Polyphenol-enriched fruit extracts containing epicatechin exhibited a significant anti-allergic effect in vivo. This effect was unambiguously attributed to epicatechin, as oral administration of this purified polyphenol to sensitised mice by inclusion in their diet modulated allergy symptoms in a dose-dependent manner. Immune parameters were also affected by the administration of epicatechin. Bioavailability measurements in plasma indicated that the attenuation of allergy symptoms could be due to the higher concentrations of bioavailable epicatechin metabolites. In conclusion, epicatechin is a key bioactive polyphenol that has the ability to modulate allergy outcomes in sensitised mice.
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Xu H, Wang X, Veazey RS. Th17 Cells Coordinate with Th22 Cells in Maintaining Homeostasis of Intestinal Tissues and both are Depleted in SIV-Infected Macaques. ACTA ACUST UNITED AC 2014; 5. [PMID: 25364618 PMCID: PMC4215515 DOI: 10.4172/2155-6113.1000302] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Th17 and Th22 cells are thought to function as innate regulators of mucosal antimicrobial responses, tissue inflammation and mucosal integrity, yet their role in persistent SIV infection is still unclear. Here we compared Th17 and Th22 cells in their phenotype, effector/cytokine function, and frequency in blood and intestinal mucosal tissues, and correlate levels with mucosal damage in SIV-infected rhesus macaques. We found that Th17/Th22 cells share similar features in that both highly produce TNF-α and IL-2 and express CCR5 in intestinal tissues; yet very few show cytotoxic functions, as evidenced by lack of IFN-γ and granzyme B production. Further, Th17/Th22 cells display distinct tissue-specific distributions. Both Th17 and Th22 cells and cytokine secretion were significantly depleted in both blood and intestine in chronically SIV-infected macaques. The frequency of Th17 and Th22 cells in the intestine positively correlated with percentages of intestinal CD4+ T cells and negatively with damage to intestinal mucosa, and plasma viral loads in SIV infection. These findings indicate Th17 and Th22 cells share considerable functions, and may coordinate in innate mucosal immune responses, and their regional loss in the intestine may be associated with local mucosal immune dysfunction in persistent HIV/SIV infection.
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Affiliation(s)
- Huanbin Xu
- Tulane National Primate Research Center, Tulane University School of Medicine, 18703 Three Rivers Road Covington, LA 70433, USA
| | - Xiaolei Wang
- Tulane National Primate Research Center, Tulane University School of Medicine, 18703 Three Rivers Road Covington, LA 70433, USA
| | - Ronald S Veazey
- Tulane National Primate Research Center, Tulane University School of Medicine, 18703 Three Rivers Road Covington, LA 70433, USA
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Duluc D, Gannevat J, Anguiano E, Zurawski S, Carley M, Boreham M, Stecher J, Dullaers M, Banchereau J, Oh S. Functional diversity of human vaginal APC subsets in directing T-cell responses. Mucosal Immunol 2013; 6:626-38. [PMID: 23131784 PMCID: PMC3568194 DOI: 10.1038/mi.2012.104] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Human vaginal mucosa is the major entry site of sexually transmitted pathogens and thus has long been attractive as a site for mounting mucosal immunity. It is also known as a tolerogenic microenvironment. Here, we demonstrate that immune responses in the vagina can be orchestrated by the functional diversity of four major antigen-presenting cell (APC) subsets. Langerhans cells (LCs) and CD14(-) lamina propria-dendritic cells (LP-DCs) polarize CD4(+) and CD8(+) T cells toward T-helper type 2 (Th2), whereas CD14(+) LP-DCs and macrophages polarize CD4(+) T cells toward Th1. Both LCs and CD14(-) LP-DCs are potent inducers of Th22. Owing to their functional specialties and the different expression levels of pattern-recognition receptors on the APC subsets, microbial products do not bias them to elicit common types of immune responses (Th1 or Th2). To evoke desired types of adaptive immune responses in the human vagina, antigens may need to be targeted to proper APC subsets with right adjuvants.
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Affiliation(s)
- Dorothée Duluc
- Baylor Institute for Immunology Research, Dallas, TX 75204, USA
| | - Julien Gannevat
- Baylor Institute for Immunology Research, Dallas, TX 75204, USA
| | | | - Sandra Zurawski
- Baylor Institute for Immunology Research, Dallas, TX 75204, USA
| | - Michael Carley
- Department of Obstetrics and Gynecology, Baylor University Medical Center, 3600 Gaston Avenue, Dallas, TX 75246, USA
| | - Muriel Boreham
- Department of Obstetrics and Gynecology, Baylor University Medical Center, 3600 Gaston Avenue, Dallas, TX 75246, USA
| | - Jack Stecher
- Department of Obstetrics and Gynecology, Baylor University Medical Center, 3600 Gaston Avenue, Dallas, TX 75246, USA
| | | | | | - SangKon Oh
- Baylor Institute for Immunology Research, Dallas, TX 75204, USA
,INSERM U955, 3434 Live Oak, Dallas, TX 75204, USA
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Abstract
Interleukin-22 (IL-22) has important functions in host defense at mucosal surfaces as well as in tissue repair. It is unique as a cytokine that is produced by immune cells, including T-helper (Th) cell subsets and innate lymphocytes, but acts only on non-hematopoietic stromal cells, in particular epithelial cells, keratinocytes, and hepatocytes. Although IL-22 is beneficial to the host in many infectious and inflammatory disorders, depending on the target tissue it can be pathogenic due to its inherent pro-inflammatory properties, which are further enhanced when IL-22 is released together with other pro-inflammatory cytokines, in particular IL-17. To avoid pathology, IL-22 and IL-17 production have to be controlled tightly and independently. While common factors such as signal transducer and activator of transcription 3 (STAT3) and retinoid orphan receptor γt (RORγt) drive the expression of both cytokines, other factors, such as c-Maf act specifically on IL-22 and enable the separate expression of either cytokine. Here, we discuss the production of IL-22 from various T-cell populations as well as protective versus pathogenic roles of IL-22. Finally, we focus on recent advances in our understanding of the molecular regulation of IL-22 in T cells.
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Affiliation(s)
- Sascha Rutz
- Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
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Deoxynivalenol as a new factor in the persistence of intestinal inflammatory diseases: an emerging hypothesis through possible modulation of Th17-mediated response. PLoS One 2013; 8:e53647. [PMID: 23326479 PMCID: PMC3542340 DOI: 10.1371/journal.pone.0053647] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 12/03/2012] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND/AIMS Deoxynivalenol (DON) is a mycotoxin produced by Fusarium species which is commonly found in temperate regions worldwide as a natural contaminant of cereals. It is of great concern not only in terms of economic losses but also in terms of animal and public health. The digestive tract is the first and main target of this food contaminant and it represents a major site of immune tolerance. A finely tuned cross-talk between the innate and the adaptive immune systems ensures the homeostatic equilibrium between the mucosal immune system and commensal microorganisms. The aim of this study was to analyze the impact of DON on the intestinal immune response. METHODOLOGY Non-transformed intestinal porcine epithelial cells IPEC-1 and porcine jejunal explants were used to investigate the effect of DON on the intestinal immune response and the modulation of naive T cells differentiation. Transcriptomic proteomic and flow cytometry analysis were performed. RESULTS DON induced a pro-inflammatory response with a significant increase of expression of mRNA encoding for IL-8, IL-1α and IL-1β, TNF-α in all used models. Additionally, DON significantly induced the expression of genes involved in the differentiation of Th17 cells (STAT3, IL-17A, IL-6, IL-1β) at the expenses of the pathway of regulatory T cells (Treg) (FoxP3, RALDH1). DON also induced genes related to the pathogenic Th17 cells subset such as IL-23A, IL-22 and IL-21 and not genes related to the regulatory Th17 cells (rTh17) such as TGF-β and IL-10. CONCLUSION DON triggered multiple immune modulatory effects which could be associated with an increased susceptibility to intestinal inflammatory diseases.
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Inflammatory monocyte recruitment is regulated by interleukin-23 during systemic bacterial infection. Infect Immun 2012; 80:4099-105. [PMID: 22966045 DOI: 10.1128/iai.00589-12] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Listeria monocytogenes is a gram-positive intracellular pathogen that causes meningitis and septicemia in immunocompromised individuals and spontaneous abortion in pregnant women. The innate immune response against L. monocytogenes is primarily mediated by neutrophils and monocytes. Interleukin-23 (IL-23) is an important proinflammatory cytokine well known for its role in neutrophil recruitment in various infectious and autoimmune diseases. We have previously shown that IL-23 is required for host resistance against L. monocytogenes and for neutrophil recruitment to the liver, but not the spleen, during infection. Despite efficient neutrophil recruitment to the spleen, IL-23p19 knockout (KO) mice have an increased bacterial burden in this organ, suggesting that IL-23 may regulate the recruitment/function of another cell type to the spleen. In this study, we show that specific depletion of neutrophils abrogated the differences in bacterial burdens in the livers but not the spleens of C57BL/6 (B6) and IL-23p19 KO mice. Interestingly, L. monocytogenes-infected IL-23p19 KO mice had fewer monocytes in the spleen than B6 mice, as well as a reduction in the monocyte-recruiting chemokines CCL2 and CCL7. Additionally, the overall concentrations of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO(•)), as well as the percentages and total numbers of monocytes producing TNF-α and NO(•), were reduced in IL-23p19 KO mice compared to levels in B6 mice, leading to increased bacterial burdens in the spleens of L. monocytogenes-infected IL-23p19 KO mice. Collectively, our data establish that IL-23 is required for the optimal recruitment of TNF-α- and NO(•)-producing inflammatory monocytes, thus revealing a novel mechanism by which this proinflammatory cytokine provides protection against bacterial infection.
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Brosnahan MM, Miller DC, Adams M, Antczak DF. IL-22 is expressed by the invasive trophoblast of the equine (Equus caballus) chorionic girdle. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2012; 188:4181-7. [PMID: 22490443 PMCID: PMC3746837 DOI: 10.4049/jimmunol.1103509] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The invasive trophoblast cells of the equine placenta migrate into the endometrium to form endometrial cups, dense accumulations of trophoblast cells that produce equine chorionic gonadotropin between days 40 and 120 of normal pregnancy. The mechanisms by which the trophoblast cells invade the endometrium while evading maternal immune destruction are poorly defined. A gene expression microarray analysis performed on placental tissues obtained at day 34 of gestation revealed a >900-fold upregulation of mRNA encoding the cytokine IL-22 in chorionic girdle relative to noninvasive chorion. Quantitative RT-PCR assays were used to verify high expression of IL-22 in chorionic girdle. Additional quantitative RT-PCR analysis showed a striking increase in IL-22 mRNA expression in chorionic girdle from days 32 to 35 and an absence of IL-22 expression in other conceptus tissues. Bioinformatic analysis and cDNA sequencing confirmed the predicted length of horse IL-22, which carries a 3' extension absent in IL-22 genes of humans and mice, but present in the cow and pig. Our discovery of IL-22 in the chorionic girdle is a novel finding, as this cytokine has been previously reported in immune cells only. IL-22 has immunoregulatory functions, with primary action on epithelial cells. mRNA of IL-22R1 was detected in pregnant endometrium at levels similar to other equine epithelia. Based upon these findings, we hypothesize that IL-22 cytokine produced by the chorionic girdle binds IL-22R1 on endometrium, serving as a mechanism of fetal-maternal communication by modulating endometrial responses to trophoblast invasion.
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Affiliation(s)
- Margaret M Brosnahan
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
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Hofmann S, Rösen-Wolff A, Tsokos G, Hedrich C. Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol 2012; 143:116-27. [DOI: 10.1016/j.clim.2012.02.005] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 02/24/2012] [Accepted: 02/26/2012] [Indexed: 12/16/2022]
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Abstract
OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2−/−) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3β/γ 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.
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Feinen B, Russell MW. Contrasting Roles of IL-22 and IL-17 in Murine Genital Tract Infection by Neisseria gonorrhoeae. Front Immunol 2012; 3:11. [PMID: 22566897 PMCID: PMC3342391 DOI: 10.3389/fimmu.2012.00011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 01/18/2012] [Indexed: 01/21/2023] Open
Abstract
Murine genital tract infection with Neisseria gonorrhoeae has previously been found to induce IL-17 which is important in both recruitment of neutrophils and prompt clearance of the infection. As IL-22 is another Th17-related cytokine that has been implicated in the immune responses in several infection models, we investigated its role in vaginal gonococcal infection of mice. Production of IL-22 was observed in response to stimulation with N. gonorrhoeae in both mouse splenic mononuclear cells and vaginal tissue explants cultured ex vivo. Tissue from mice genetically deficient in IL-22 showed diminished production of IL-6 and the CXC chemokine KC in response to N. gonorrhoeae, whereas IL-17 and the chemokines LIX and MIP-2α were produced to the same extent as in wild-type tissue. IL-22-deficient mice were unexpectedly resistant to genital tract infection with N. gonorrhoeaein vivo, but showed no change in the influx of neutrophils to the site of infection. These results reveal divergent roles for IL-17 and IL-22 in response to gonococcal infection.
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Affiliation(s)
- Brandon Feinen
- Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo Buffalo, NY, USA
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42
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Ciccia F, Guggino G, Rizzo A, Ferrante A, Raimondo S, Giardina A, Dieli F, Campisi G, Alessandro R, Triolo G. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome. Ann Rheum Dis 2012; 71:295-301. [PMID: 21979002 DOI: 10.1136/ard.2011.154013] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES In chronic inflammatory disorders, interleukin (IL)-22 may act either as a protective or as a pro-inflammatory cytokine. At mucosal sites, IL-22 is mainly produced by CD4(+) T cells and by a subset of mucosal natural killer (NK) cells expressing the receptor NKp44 (NKp44(+) NK cells). The aim of this study was to investigate the IL-22 expression in the salivary glands of patients with primary Sjögren's syndrome (pSS). METHODS Minor salivary gland biopsies were obtained from 19 patients with pSS and 16 with non-specific chronic sialoadenitis. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-17, IL-22, IL-23 and STAT3 (signal transducer and activator of transcription) was performed on salivary glands from patients and controls. The cellular sources of IL-22 among infiltrating inflammatory cells were also determined by fluorescence-activated cell sorting analysis and immunohistochemistry. RESULTS IL-22, IL-23 and IL-17 were significantly increased at both protein and mRNA levels in the inflamed salivary glands of patients with pSS. STAT3 mRNA and the tyrosine phosphorylated corresponding protein were also significantly increased in pSS. Th17 and NKp44(+) NK cells were the major cellular sources of IL-22 in patients with pSS. CONCLUSIONS Our results suggest that, together with IL-17 and IL-23, IL-22 may play a pro-inflammatory role in the pathogenesis of pSS.
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Affiliation(s)
- Francesco Ciccia
- Dipartimento Biomedico di Medicina Interna e Specialistiche, Sezione di Reumatologia, Università di Palermo, Italy
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43
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Xu M, Morishima N, Mizoguchi I, Chiba Y, Fujita K, Kuroda M, Iwakura Y, Cua DJ, Yasutomo K, Mizuguchi J, Yoshimoto T. Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production. Eur J Immunol 2011; 41:2828-39. [PMID: 21953641 DOI: 10.1002/eji.201141291] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Revised: 07/04/2011] [Accepted: 07/12/2011] [Indexed: 01/16/2023]
Abstract
IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting IL-17 and IL-22. Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19- and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-γ and TNF-α. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.
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Affiliation(s)
- Mingli Xu
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
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Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 2011; 29:71-109. [PMID: 21166540 DOI: 10.1146/annurev-immunol-031210-101312] [Citation(s) in RCA: 1398] [Impact Index Per Article: 99.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The IL-10 family of cytokines consists of nine members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and the more distantly related IL-28A, IL-28B, and IL-29. Evolutionarily, IL-10 family cytokines emerged before the adaptive immune response. These cytokines elicit diverse host defense mechanisms, especially from epithelial cells, during various infections. IL-10 family cytokines are essential for maintaining the integrity and homeostasis of tissue epithelial layers. Members of this family can promote innate immune responses from tissue epithelia to limit the damage caused by viral and bacterial infections. These cytokines can also facilitate the tissue-healing process in injuries caused by infection or inflammation. Finally, IL-10 itself can repress proinflammatory responses and limit unnecessary tissue disruptions caused by inflammation. Thus, IL-10 family cytokines have indispensable functions in many infectious and inflammatory diseases.
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Affiliation(s)
- Wenjun Ouyang
- Department of Immunology, Genentech, Inc., South San Francisco, California 94080, USA.
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45
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Liu Y, Feinen B, Russell MW. New concepts in immunity to Neisseria gonorrhoeae: innate responses and suppression of adaptive immunity favor the pathogen, not the host. Front Microbiol 2011; 2:52. [PMID: 21833308 PMCID: PMC3153028 DOI: 10.3389/fmicb.2011.00052] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 03/08/2011] [Indexed: 12/31/2022] Open
Abstract
It is well-known that gonorrhea can be acquired repeatedly with no apparent development of protective immunity arising from previous episodes of infection. Symptomatic infection is characterized by a purulent exudate, but the host response mechanisms are poorly understood. While the remarkable antigenic variability displayed by Neisseria gonorrhoeae and its capacity to inhibit complement activation allow it to evade destruction by the host's immune defenses, we propose that it also has the capacity to avoid inducing specific immune responses. In a mouse model of vaginal gonococcal infection, N. gonorrhoeae elicits Th17-driven inflammatory–immune responses, which recruit innate defense mechanisms including an influx of neutrophils. Concomitantly, N. gonorrhoeae suppresses Th1- and Th2-dependent adaptive immunity, including specific antibody responses, through a mechanism involving TGF-β and regulatory T cells. Blockade of TGF-β alleviates the suppression of specific anti-gonococcal responses and allows Th1 and Th2 responses to emerge with the generation of immune memory and protective immunity. Genital tract tissues are naturally rich in TGF-β, which fosters an immunosuppressive environment that is important in reproduction. In exploiting this niche, N. gonorrhoeae exemplifies a well-adapted pathogen that proactively elicits from its host innate responses that it can survive and concomitantly suppresses adaptive immunity. Comprehension of these mechanisms of gonococcal pathogenesis should allow the development of novel approaches to therapy and facilitate the development of an effective vaccine.
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Affiliation(s)
- Yingru Liu
- Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo Buffalo, NY, USA
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Graham AC, Carr KD, Sieve AN, Indramohan M, Break TJ, Berg RE. IL-22 production is regulated by IL-23 during Listeria monocytogenes infection but is not required for bacterial clearance or tissue protection. PLoS One 2011; 6:e17171. [PMID: 21347242 PMCID: PMC3039664 DOI: 10.1371/journal.pone.0017171] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 01/23/2011] [Indexed: 01/07/2023] Open
Abstract
Listeria monocytogenes (LM) is a gram-positive bacterium that is a common contaminant of processed meats and dairy products. In humans, ingestion of LM can result in intracellular infection of the spleen and liver, which can ultimately lead to septicemia, meningitis, and spontaneous abortion. Interleukin (IL)-23 is a cytokine that regulates innate and adaptive immune responses by inducing the production of IL-17A, IL-17F, and IL-22. We have recently demonstrated that the IL-23/IL-17 axis is required for optimal recruitment of neutrophils to the liver, but not the spleen, during LM infection. Furthermore, these cytokines are required for the clearance of LM during systemic infection. In other infectious models, IL-22 induces the secretion of anti-microbial peptides and protects tissues from damage by preventing apoptosis. However, the role of IL-22 has not been thoroughly investigated during LM infection. In the present study, we show that LM induces the production of IL-22 in vivo. Interestingly, IL-23 is required for the production of IL-22 during primary, but not secondary, LM infection. Our findings suggest that IL-22 is not required for clearance of LM during primary or secondary infection, using both systemic and mucosal models of infection. IL-22 is also not required for the protection of LM infected spleens and livers from organ damage. Collectively, these data indicate that IL-22 produced during LM infection must play a role other than clearance of LM or protection of tissues from pathogen- or immune-mediated damage.
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Affiliation(s)
- Amy C. Graham
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Karen D. Carr
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Amy N. Sieve
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Mohanalaxmi Indramohan
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Timothy J. Break
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Rance E. Berg
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
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Abstract
IL-22, an IL-10 family cytokine, is produced by different leukocyte subsets, including T cells, NK cells and lymphoid tissue inducer (LTi) cells. IL-22 mediates the crosstalk between leukocytes and tissue epithelia because its receptor is preferentially expressed on various tissue epithelial cells. IL-22 is essential for host defense against infections of extracellular pathogens, such as bacteria and yeasts, by eliciting various innate defensive mechanisms from tissue epithelial cells and promoting wound-healing responses. In autoimmune diseases, however, diverse tissue microenvironments and underlying pathogenic mechanisms may result in opposing contributions of IL-22 in disease progression. For example, in psoriasis, IL-22 can synergize with other proinflammatory cytokines to induce many of the pathogenic phenotypes from keratinocytes and exacerbate disease progression. In contrast, IL-22 plays a beneficial role in IBD by enhancing barrier integrity and epithelial innate immunity of intestinal tract.
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Affiliation(s)
- Wenjun Ouyang
- Department of Immunology, Genentech, Inc., 1 DNA Way, M/S 34, South San Francisco, CA 94080, USA.
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48
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Abstract
PURPOSE OF REVIEW To summarize our current understanding of the regulation of Th17 cells in pathogenic and nonpathogenic lentiviral infections. RECENT FINDINGS It has been shown that Th17 cells, a recently identified T helper-cell subset deemed critical for antimicrobial mucosal immunity, are preferentially depleted in the gastrointestinal tracts of human immunodeficiency virus (HIV)-infected humans and simian immunodeficiency virus (SIV)-infected rhesus and pigtailed (PTMs) macaques. In contrast, Th17 cells are preserved at healthy levels in monkey species that are natural hosts for SIV, such as sooty mangabeys or African green monkeys (AGMs), which maintain mucosal immunity and remain AIDS free. These findings suggest that preservation of Th17 cells (or lack thereof) may be central in determining the pathogenic or nonpathogenic outcome of HIV/SIV infection. SUMMARY A preferential depletion of mucosal Th17 cells is a feature that distinguishes pathogenic HIV infection of humans from nonprogressive SIV infection of sooty mangabeys and AGMs. The exact mechanism accounting for this different phenotype is still unclear. To understand how natural hosts for SIV preserve Th17 cells and mucosal immunity might be central to the development of therapeutic interventions aimed at improving mucosal immunity in HIV-infected individuals.
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49
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Russell MW, Mestecky J. Tolerance and protection against infection in the genital tract. Immunol Invest 2010; 39:500-25. [PMID: 20450289 DOI: 10.3109/08820131003674834] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The genital tract is a unique immunological environment that must support the reproductive function and resist infection. Particularly in the female tract, immunoregulatory and immunosuppressive activities that permit the growth of the fetus create an environment that can readily be exploited by microbes that have become well-adapted to this location. Cellular and molecular mediators of immune responses differ from those found at other mucosal surfaces. Mechanisms of immune response induction and delivery, as well as immune effector functions at the genital mucosae need to be considered in the development of vaccines against infections of the genital tract.
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Affiliation(s)
- Michael W Russell
- Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, Buffalo, New York 14214, USA.
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50
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Wilson MS, Feng CG, Barber DL, Yarovinsky F, Cheever AW, Sher A, Grigg M, Collins M, Fouser L, Wynn TA. Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 184:4378-90. [PMID: 20220096 PMCID: PMC3170015 DOI: 10.4049/jimmunol.0903416] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
IL-22 is a member of the IL-10 cytokine family and signals through a heterodimeric receptor composed of the common IL-10R2 subunit and the IL-22R subunit. IL-10 and IL-22 both activate the STAT3 signaling pathway; however, in contrast to IL-10, relatively little is known about IL-22 in the host response to infection. In this study, using IL-22(-/-) mice, neutralizing Abs to IL-22, or both, we show that IL-22 is dispensable for the development of immunity to the opportunistic pathogens Toxoplasma gondii and Mycobacterium avium when administered via the i.p. or i.v. route, respectively. IL-22 also played little to no role in aerosol infections with Mycobacterium tuberculosis and in granuloma formation and hepatic fibrosis following chronic percutaneous infections with the helminth parasite Schistosoma mansoni. A marked pathogenic role for IL-22 was, however, identified in toxoplasmosis when infections were established by the natural oral route. Anti-IL-22 Ab-treated mice developed significantly less intestinal pathology than control Ab-treated mice even though both groups displayed similar parasite burdens. The decreased gut pathology was associated with reduced IL-17A, IL-17F, TNF-alpha, and IFN-gamma expression. In contrast to the prior observations of IL-22 protective effects in the gut, these distinct findings with oral T. gondii infection demonstrate that IL-22 also has the potential to contribute to pathogenic inflammation in the intestine. The IL-22 pathway has emerged as a possible target for control of inflammation in certain autoimmune diseases. Our findings suggest that few if any infectious complications would be expected with the suppression of IL-22 signaling.
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MESH Headings
- Animals
- Genetic Predisposition to Disease
- Inflammation Mediators/physiology
- Interleukins/deficiency
- Interleukins/physiology
- Intestinal Diseases, Parasitic/genetics
- Intestinal Diseases, Parasitic/immunology
- Intestinal Diseases, Parasitic/pathology
- Liver Diseases, Parasitic/genetics
- Liver Diseases, Parasitic/immunology
- Liver Diseases, Parasitic/pathology
- Meningitis/genetics
- Meningitis/immunology
- Meningitis/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Mycobacterium avium-intracellulare Infection/genetics
- Mycobacterium avium-intracellulare Infection/immunology
- Schistosomiasis mansoni/genetics
- Schistosomiasis mansoni/immunology
- Toxoplasmosis, Animal/genetics
- Toxoplasmosis, Animal/immunology
- Tuberculosis/genetics
- Tuberculosis/immunology
- Interleukin-22
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Affiliation(s)
- Mark S. Wilson
- Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Carl G. Feng
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Daniel L. Barber
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Felix Yarovinsky
- University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
| | | | - Alan Sher
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Michael Grigg
- Molecular Parasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Mary Collins
- Wyeth Research-Inflammation, Cambridge, MA 02140
| | | | - Thomas A. Wynn
- Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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