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1
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Song Z, Wu J, Jiang T, He R, Wen H. The protective effect of the vagus nerve-α7nAChR-IL-22 pathway on acute liver injury. Cytokine 2025; 186:156840. [PMID: 39705885 DOI: 10.1016/j.cyto.2024.156840] [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: 08/14/2024] [Revised: 11/14/2024] [Accepted: 12/14/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Acute liver injury is a common pathological feature of various clinical diseases, and prolonged liver damage can lead to fibrosis and even liver failure. Studies have reported that the vagus nerve can repair liver injury through the regulation of the cholinergic anti-inflammatory pathway. However, there is limited research on the regulation of interleukin-22 and its role in liver injury. This study aimed to investigate the regulatory effect of vagus nerve receptor α7nAChR on interleukin-22 and whether this regulatory axis can protect against liver injury. METHODS Rats and the human liver cell line L-02 were treated with carbon tetrachloride to simulate acute liver injury. The experimental groups were divided as follows: control group, model group, model + PNU282987 group, model + MLA group, and MLA group. After the intervention, blood samples, liver tissues, and cells were collected to assess liver function (AST, ALT), inflammation (TNF-α, IL-6,), α7nAChR and interleukin-22 concentrations, apoptosis levels (Bax, BCL-2), and proliferation markers (Ki-67, PCNA) using quantitative real time PCR, Western blot, immunohistochemistry and ELISA. RESULTS The results indicated that carbon tetrachloride intervention led to compensatory increases in interleukin-22 while inhibition of α7nAChR decreased interleukin-22 concentrations and exacerbated the injury marked by high levels of AST, ALT and TNF-α,IL-6. Exogenous administration of a vagus nerve agonist alleviated liver injury and was accompanied by an increase in interleukin-22 levels. In rescue experiments, simultaneous inhibition of vagus nerve receptors and administration of exogenous interleukin-22 reduced liver injury and significantly enhanced liver regeneration. Conversely, activation of vagus nerve receptors while inhibiting interleukin-22 aggravated liver injury. CONCLUSION This study confirms that vagus nerve receptor α7nAChR can promote liver regeneration and protect against carbon tetrachloride-induced liver injury by regulating interleukin-22.
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Affiliation(s)
- Zhihao Song
- Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jing Wu
- Department of Liver Transplantation & Laparoscopic Surgery, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Tiemin Jiang
- Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Rongdong He
- Department of Liver Transplantation & Laparoscopic Surgery, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hao Wen
- Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China; State Key Laboratory of Pathogenesis, Prevention, Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China.
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2
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Klepp LI, Bigi MM, Villafañe L, Blanco FC, Malinge L P, Bigi F. Production of functional bovine IL-22 in a mammalian episomal expression system. Vet Immunol Immunopathol 2025; 279:110863. [PMID: 39615285 DOI: 10.1016/j.vetimm.2024.110863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/13/2024] [Accepted: 11/25/2024] [Indexed: 01/07/2025]
Abstract
Interleukin 22 is a member of the interleukin-10 superfamily of cytokines. This protein has a dual role as an inflammatory and anti-inflammatory molecule dependent on the context. IL-22 is produced mainly by immune cells and seems to have non-hematopoietic cells as its target. In this work, we report the production of bovine IL-22 for the first time in a semi-stable expression system in mammalian cells. We showed that this recombinant IL-22 possesses biological activity in bovine macrophages infected with Mycobacterium bovis and is easy to produce in large quantities. Given its role in the defence against infections, the IL-22 produced in this work has potential applications in scientific research as well as in immunotherapy to treat diseases in cattle.
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Affiliation(s)
- Laura I Klepp
- Instituto de Agrobiotecnología y Biología Molecular (IABIMO), UEDD INTA-CONICET, Argentina; Instituto de Biotecnología, CICVyA, Instituto Nacional de Tecnología Agropecuaria (Institute of Biotechnology, National Institute of Agricultural Technology, Argentina), Argentina.
| | | | - Luciana Villafañe
- Instituto de Agrobiotecnología y Biología Molecular (IABIMO), UEDD INTA-CONICET, Argentina; Instituto de Biotecnología, CICVyA, Instituto Nacional de Tecnología Agropecuaria (Institute of Biotechnology, National Institute of Agricultural Technology, Argentina), Argentina.
| | - Federico C Blanco
- Instituto de Agrobiotecnología y Biología Molecular (IABIMO), UEDD INTA-CONICET, Argentina; Instituto de Biotecnología, CICVyA, Instituto Nacional de Tecnología Agropecuaria (Institute of Biotechnology, National Institute of Agricultural Technology, Argentina), Argentina.
| | | | - Fabiana Bigi
- Instituto de Agrobiotecnología y Biología Molecular (IABIMO), UEDD INTA-CONICET, Argentina; Instituto de Biotecnología, CICVyA, Instituto Nacional de Tecnología Agropecuaria (Institute of Biotechnology, National Institute of Agricultural Technology, Argentina), Argentina.
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3
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Liu SZ, Xie JH, Yan BJ, Wang J. Knowledge mapping and research trends of IL-22 from 2014 to 2023: A bibliometric analysis. Hum Vaccin Immunother 2024; 20:2426321. [PMID: 39540219 PMCID: PMC11572295 DOI: 10.1080/21645515.2024.2426321] [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: 07/02/2024] [Revised: 10/19/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
Although IL-22 has been extensively studied, a comprehensive and systematic bibliometric analysis has not yet been conducted on it. This article reviews the research progress of IL-22 using bibliometric methods. On May 20, 2024, publications related to IL-22 were identified and selected from the Web of Science Core Collection (WoSCC) database. CiteSpace and VOSviewer are beneficial for IL-22 bibliometric and knowledge graph analysis. From January 1, 2014 to December 31, 2023, 25134 authors from 4206 institutions in 106 countries published 3943 articles on IL-22 research in 940 academic journals. During this period, the number of articles steadily increased. The United States and China are the main contributors to this research field, with the most active institutions being the Medical Research Institute (INSERM) led by De la Sante et al. and the University of California system. The most prolific journal is Frontiers of Immunology, and it is also the journal with the most citations. Guttman Yassky, E. has published the most articles, and Guttman Yassky, E. is also the most frequently cited. The main areas of these publications are immunology and cell biology. After analysis, the high-frequency keywords of IL-22 research involve molecular biology (IL-17) and immune response (T cells) Th17 cells and diseases (autoimmune diseases, cancer). Among them, the involvement of interleukin-22 in microbial populations and cancer cell spread has strong research potential and is currently a hot research topic. Since 2014, IL-22 has received significant attention in scientific research as a key immune regulatory factor. China is at the forefront of research in this field, followed closely by the United States. At present, breakthrough progress is being made in the research of immunotherapy, and in-depth study of IL-22 and its signal transduction mechanisms is crucial for understanding its biological functions. Meanwhile, exploring new possibilities for IL-22 as a therapeutic target will help develop more effective treatment strategies. This study can provide scholars with research directions related to IL-22.
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Affiliation(s)
- Shu-Zhen Liu
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jie-Hong Xie
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Bing-Ju Yan
- Department of Cardiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jun Wang
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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4
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Yu F, Xie S, Wang T, Huang Y, Zhang H, Peng D, Feng Y, Yang Y, Zhang Z, Zhu Y, Meng Z, Zhang R, Li X, Yin H, Xu J, Hu C. Pancreatic β cell interleukin-22 receptor subunit alpha 1 deficiency impairs β cell function in type 2 diabetes via cytochrome b5 reductase 3. Cell Rep 2024; 43:115057. [PMID: 39675006 DOI: 10.1016/j.celrep.2024.115057] [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: 06/04/2024] [Revised: 11/10/2024] [Accepted: 11/21/2024] [Indexed: 12/17/2024] Open
Abstract
Impaired β cell function is a hallmark of type 2 diabetes (T2D), but the underlying cellular signaling machineries that regulate β cell function remain unknown. Here, we identify that the interleukin-22 receptor subunit alpha 1 (IL-22RA1), known as a co-receptor for IL-22, is downregulated in human and mouse T2D β cells. Mice with β cell Il22ra1 knockout (Il22ra1βKO) exhibit defective insulin secretion and impaired glucose tolerance after being fed a high-fat diet (HFD) or an HFD/low dose of streptozotocin (STZ). Mechanistically, β cell IL-22RA1 deficiency inhibits cytochrome b5 reductase 3 (CYB5R3) expression via the IL-22RA1/signal transducer and activator of the transcription 3 (STAT3)/c-Jun axis, thereby impairing mitochondrial function and reducing β cell identity. Overexpression of CYB5R3 reinstates mitochondrial function, β cell identity, and insulin secretion in Il22ra1βKO mice. Moreover, the pharmacological activation of CYB5R3 with tetrahydroindenoindole restores insulin secretion in Il22ra1βKO mice, IL-22RA1-knockdown human islets, and Min6 cells. In conclusion, these findings suggest an important role of IL-22RA1 in preserving β cell function in T2D, which offers a potential therapeutic target for treating diabetes.
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Affiliation(s)
- Fan Yu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Shuting Xie
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Tongyu Wang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yeping Huang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Hong Zhang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Danfeng Peng
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yifan Feng
- Organ Transplant Center, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
| | - Yumei Yang
- Department of Endocrinology and Metabolism, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Zheyu Zhang
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Zhuoxian Meng
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Xiaomu Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China.
| | - Hao Yin
- Organ Transplant Center, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China.
| | - Jie Xu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Cheng Hu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China.
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5
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Zhao S, Gao K, Han H, Stenzel M, Yin B, Song H, Lawanprasert A, Nielsen JE, Sharma R, Arogundade OH, Pimcharoen S, Chen YJ, Paul A, Tuma J, Collins MG, Wyle Y, Cranick MG, Burgstone BW, Perez BS, Barron AE, Smith AM, Lee HY, Wang A, Murthy N. Acid-degradable lipid nanoparticles enhance the delivery of mRNA. NATURE NANOTECHNOLOGY 2024; 19:1702-1711. [PMID: 39179796 DOI: 10.1038/s41565-024-01765-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 07/19/2024] [Indexed: 08/26/2024]
Abstract
Lipid nanoparticle (LNP)-mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates, high toxicity and long tissue persistence times. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problems limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Here we present an acid-degradable linker termed 'azido-acetal' that hydrolyses in endosomes within minutes and enables the production of RD-LNPs. Acid-degradable lipids composed of polyethylene glycol lipids, anionic lipids and cationic lipids were synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improved the performance of LNP-mRNA complexes in vitro and in vivo. Collectively, RD-LNPs delivered mRNA more efficiently to the liver, lung, spleen and brains of mice and to haematopoietic stem and progenitor cells in vitro than conventional LNPs. These experiments demonstrate that engineering LNP hydrolysis rates in vivo has great potential for expanding the medical applications of LNPs.
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Affiliation(s)
- Sheng Zhao
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Kewa Gao
- Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA
| | - Hesong Han
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA.
| | - Michael Stenzel
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Boyan Yin
- Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA
| | - Hengyue Song
- Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA
| | - Atip Lawanprasert
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Josefine Eilsø Nielsen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
- Department of Bioengineering, School of Medicine, Stanford University, Stanford, CA, USA
| | - Rohit Sharma
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Opeyemi H Arogundade
- Department of Bioengineering and Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Sopida Pimcharoen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Yu-Ju Chen
- Department of Cellular and Integrative Physiology, University of Texas, Health Science Center at San Antonio, San Antonio, TX, USA
| | - Abhik Paul
- Department of Cellular and Integrative Physiology, University of Texas, Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jan Tuma
- Department of Cellular and Integrative Physiology, University of Texas, Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, Plzen, Czech Republic
| | - Michael G Collins
- Department of Cellular and Integrative Physiology, University of Texas, Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yofiel Wyle
- Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA
| | - Matileen Grace Cranick
- Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA
| | - Benjamin W Burgstone
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Barbara S Perez
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Annelise E Barron
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Andrew M Smith
- Department of Bioengineering and Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Hye Young Lee
- Department of Cellular and Integrative Physiology, University of Texas, Health Science Center at San Antonio, San Antonio, TX, USA
| | - Aijun Wang
- Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA.
| | - Niren Murthy
- Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA.
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6
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Hunzeker ZE, Zhao L, Kim AM, Parker JM, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The role of IL-22 in cancer. Med Oncol 2024; 41:240. [PMID: 39231878 DOI: 10.1007/s12032-024-02481-8] [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: 06/23/2024] [Accepted: 08/16/2024] [Indexed: 09/06/2024]
Abstract
Interleukin-22, discovered in the year of 2000, is a pleiotropic Th17 cytokine from the IL-10 family of cytokines. IL-22 signals through the type 2 cytokine receptor complex IL-22R and predominantly activates STAT3. This pathway leads to the transcription of several different types of genes, giving IL-22 context-specific functions ranging from inducing antimicrobial peptide expression to target cell proliferation. In recent years, it has been shown that IL-22 is involved in the pathogenesis of neoplasia in some cancers through its pro-proliferative and anti-apoptotic effects. This review highlights studies with recent discoveries and conclusions drawn on IL-22 and its involvement and function in various cancers. Such a study may be helpful to better understand the role of IL-22 in cancer so that new treatment could be developed targeting IL-22.
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Affiliation(s)
- Zachary E Hunzeker
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Department of Internal Medicine, University of Texas Houston Health Science Center, Houston, TX, USA
| | - Lei Zhao
- Department of Respiratory Medicine, the 2nd People's Hospital of Hefei and Hefei Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Austin M Kim
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
| | - Jacob M Parker
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
| | - Ziwen Zhu
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Huaping Xiao
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Qian Bai
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA.
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
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7
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Guo S, Peng J, Xiao Y, Chen J, Gao R. Synergistic effects of oral inoculation with a recombinant Lactobacillus plantarum NC8 strain co-expressing interleukin-2 and interleukin-17B on the efficacy of the infectious bronchitis vaccine in chickens. Poult Sci 2024; 103:103908. [PMID: 38981363 PMCID: PMC11279255 DOI: 10.1016/j.psj.2024.103908] [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: 04/05/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 07/11/2024] Open
Abstract
Mucosal vaccination strategies are easier to implement than others in large-scale poultry farming. However, the adjuvants that are approved for veterinary use, which are predominantly aluminum- and oil-emulsion-based adjuvants, are not suitable for mucosal vaccination and carry a risk of adverse reactions. In this study, we engineered a novel Lactobacillus plantarum NC8 strain that co-expresses chicken interleukin-2 (IL-2) and IL-17B, which we designated NC8-ChIL2-17B, and evaluated its potential as an oral immunoadjuvant. The immunomodulatory properties of NC8-ChIL2-17B were evidenced by its ability to activate macrophages and inhibit the proliferation of infectious bronchitis virus (IBV) in vitro. We then confirmed its immunoadjuvant activity in vivo by orally administering NC8-ChIL2-17B along with a commercial IBV vaccine to chicks. The results indicated that NC8-ChIL2-17B enhanced the immune response elicited by the IBV vaccine and increased the levels of IBV-specific IgG and sIgA antibodies produced in response to IBV infection. Additionally, administration of NC8-ChIL2-17B promoted weight gain and beneficially modulated the gut microbiota, resulting in improved chicken performance. These findings suggest that oral administration of NC8-ChIL2-17B is a promising strategy to enhance the immune efficacy of the IBV vaccine in chickens, offering an efficacious alternative adjuvant.
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Affiliation(s)
- Shaohua Guo
- Laboratory of Infectious Diseases and Vaccine, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Junjie Peng
- Key Laboratory for Bio-resource and Eco-Environment of Education Ministry, College of Life Sciences, Sichuan University, Chengdu, 610065, PR China; National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China
| | - Yongle Xiao
- School of Medicine, Sichuan University of Arts and Science, Dazhou, 635000, PR China
| | - Jianlin Chen
- School of Laboratory Medicine/Collaborative Innovation Center of Sichuan for Elderly Care and Health, Chengdu Medical College, Chengdu, Sichuan 610500, PR China
| | - Rong Gao
- Key Laboratory for Bio-resource and Eco-Environment of Education Ministry, College of Life Sciences, Sichuan University, Chengdu, 610065, PR China.
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8
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Mehran HS, Nady S, Kassab RB, Ahmed-Farid OA, El-Hennamy RE. Recombinant Interleukin - 2 2 Immunotherapy Ameliorates Inflammation and Promotes the Release of Monoamine Neurotransmitters in the Gut-Brain Axis of Schistosoma mansoni-Infected Mice. J Neuroimmune Pharmacol 2024; 19:37. [PMID: 39052165 DOI: 10.1007/s11481-024-10133-x] [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: 09/03/2023] [Accepted: 06/08/2024] [Indexed: 07/27/2024]
Abstract
Recombinant interleukin-22 (rIL-22) has been reported as a protective agent in murine models of diseases driven by epithelial injury. Parasites have a circadian rhythm and their sensitivity to a certain drug may vary during the day. Therefore, this work aimed to investigate the effect of rIL-22 administration at different times of the day on the inflammation, oxidative status, and neurotransmitter release in the gut-brain axis of the Schistosoma mansoni-infected mice. Sixty male BALB/c mice aged six weeks weighing 25-30 g were divided into a control group (injected intraperitoneally with PBS), mice infected with 80 ± 10 cercariae of S. mansoni (infected group) then injected intraperitoneally with PBS, and rIL-22 treated groups. rIL-22 was administrated intraperitoneally (400 ng/kg) either at the onset or offset of the light phase for 14 days. IL-22 administration reduced the levels of IL-1β, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa beta (NF-κβ), and enhanced the production of IL-22 and IL-17. The treatment with IL-22 increased glutathione (GSH) and reduced malondialdehyde (MDA) and nitric oxide (NO) levels both in the ileum and brain. The B-cell lymphoma 2 (BCL2) protein level in the ileum was diminished after IL-22 administration. Brain-derived neurotrophic factor (BDNF) and neurotransmitter release (serotonin, 5HT, norepinephrine, NE, dopamine, DA, Glutamate, Glu, and -amino butyric acid, GABA) were improved by rIL-22. In conclusion, rIL-22 showed promising immunotherapy for inflammation, oxidative damage, and neuropathological signs associated with schistosomiasis. The efficacy of IL-22 increased significantly upon its administration at the time of light offset.
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Affiliation(s)
- Heba S Mehran
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Soad Nady
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Rami B Kassab
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | | | - Rehab E El-Hennamy
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt.
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9
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Yang H, Cao R, Zhou F, Wang B, Xu Q, Li R, Zhang C, Xu H. The role of Interleukin-22 in severe acute pancreatitis. Mol Med 2024; 30:60. [PMID: 38750415 PMCID: PMC11097471 DOI: 10.1186/s10020-024-00826-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/02/2024] [Indexed: 05/18/2024] Open
Abstract
Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP.
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Affiliation(s)
- Hongli Yang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China
| | - Ruofan Cao
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China
| | - Feifei Zhou
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
| | - Ben Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
| | - Qianqian Xu
- Department of Gastroenterology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong University, Ji'nan, Shandong, 250021, P.R. China
| | - Rui Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China
| | - ChunHua Zhang
- Shandong First Medical University, Ji'nan, Shandong, 250117, P.R. China
| | - Hongwei Xu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China.
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China.
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Wee VTK, Shirakawa H, Yeh SL, Yeh CL. Fermented rice bran supplementation attenuates colonic injury through modulating intestinal aryl hydrocarbon receptor and innate lymphoid cells in mice with dextran sodium sulfate-induced acute colitis. J Nutr Biochem 2024; 123:109493. [PMID: 37871768 DOI: 10.1016/j.jnutbio.2023.109493] [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: 03/10/2023] [Revised: 07/14/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023]
Abstract
This study investigated the effects of fermented rice bran (FRB) on modulating intestinal aryl hydrocarbon receptor (AhR) expression, innate lymphoid cell (ILC)3 populations, the fecal microbiota distribution, and their associations with dextran sodium sulfate (DSS)-induced acute colitis. C57BL/6 mice were assigned to four groups: 1) NC group, normal mice fed the AIN-93M diet; 2) FRB group, normal mice fed a diet supplemented with 5% FRB; 3) NCD group, DSS-treated mice fed AIN-93M; 4) FRBD group, DSS-treated mice fed a 5% FRB-supplemented diet. DSS was administered for 5 d and followed by 5 d for recovery. At the end of the experiment, mice were sacrificed. Their blood and intestinal tissues were collected. Results showed that there were no differences in colonic biological parameters and function between the NC and FRB groups. Similar fecal microbiota diversity was noted between these two groups. Compared to the non-DSS-treated groups, DSS administration led to increased intestinal permeability, enhanced inflammatory cytokine production and disease severity, whereas tight junctions and AhR, interleukin (IL)-22 expressions were downregulated, and the ILC3 population had decreased. Also, gut microbiota diversity differs from the non-DSS-treated groups and more detrimental bacterial populations exist when compared to the FRBD group. FRB supplementation in DSS-treated mice attenuated fecal microbial dysbiosis, decreased intestinal permeability, improved the barrier integrity, upregulated AhR and IL-22 expression, maintained the ILC3 population, and pathologically mitigated colonic injury. These findings suggest enhanced ILC3- and AhR-mediated functions may be partly responsible for the anti-colitis effects of FRB supplementation in DSS-induced colitis.
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Affiliation(s)
- ViVi Tang Kang Wee
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Sung-Ling Yeh
- Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiu-Li Yeh
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei, Taiwan; Research Center for Digestive Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
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11
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Liu L, Li X, Chen Y, Li YZ, Liu Z, Duan Y, Chen Y. Interleukin-22 promotes proliferation and reverses LPS-induced apoptosis and steroidogenesis attenuation in human ovarian granulosa cells: implications for polycystic ovary syndrome pathogenesis. J Matern Fetal Neonatal Med 2023; 36:2253347. [PMID: 37661176 DOI: 10.1080/14767058.2023.2253347] [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: 02/28/2023] [Revised: 08/09/2023] [Accepted: 08/24/2023] [Indexed: 09/05/2023]
Abstract
OBJECTIVE Interleukin 22 (IL-22) plays a role in inflammatory diseases. However, whether IL-22 affects the function of ovarian granulosa cells (GCs) and its relationship with Polycystic Ovary Syndrome (PCOS)remains unclear. METHODS We investigated the level of IL-22 in human follicular fluid using ELISA. The expression and localization of the IL-22 receptor 1 (IL-22R1) in GCs were investigated by RT-PCR and immunofluorescence staining, respectively. The proliferation of KGN cells (human GCs line) was assessed by CCK-8 assay and EdU assay after treatment with recombinant human IL-22 (rhIL-22) and lipopolysaccharide (LPS). Apoptosis was assessed using flow cytometry. Apoptotic proteins and steroidogenic genes were detected by western blotting. RESULTS ELISA's results showed that compared with the control group, PCOS patients showed lower expression of IL-22 in follicular fluid. Immunofluorescence showed that IL-22R1 is expressed and localized in human granulosa cell membranes. IL-22 promoted cell proliferation and reversed LPS-induced inhibition of cell proliferation. IL-22 alone did not affect apoptotic or steroidogenic protein expression, however, it reversed LPS-induced apoptosis via downregulation of Bcl-2, upregulation of Bax and cleaved caspase-3, and restoration of LPS-downregulated StAR, CYP11A1, and CYP19A1 expression. Western blotting confirmed that IL-22 activated the JAK2/STAT3 signaling. CONCLUSION IL-22 promotes cell proliferation, inhibits apoptosis, and regulates KGN cell steroidogenesis confronted with LPS, and decreased IL-22 may be involved in the development of PCOS.
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Affiliation(s)
- Linhong Liu
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xu Li
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Chen
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Zhe Li
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen Liu
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuhan Duan
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Chen
- Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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12
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Zhang W, Xu S, Zhang R, Li Z, Li N, Zhang X, Lu Y, Bian Y, Yang P, Fang F, Qin Y, Jiao X. The T H 22-mediated IL-22 deficiency associated with premature ovarian insufficiency. Am J Reprod Immunol 2023; 89:e13685. [PMID: 36752193 DOI: 10.1111/aji.13685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/12/2023] [Accepted: 01/28/2023] [Indexed: 02/09/2023] Open
Abstract
RESEARCH QUESTION Is deficiency of IL-22 associated with premature ovarian insufficiency (POI)? DESIGN Levels of IL-22 and IL-22BP, IL-22-producing T cells, and IL22RA1/IL10R2 expression were measured and compared among 29 patients with POI, 42 with precursor stage of POI (pre-POI) and 46 control women. Correlation of serum IL-22 and IL-22+ CD4+ T subsets with ovarian reserve markers were further analyzed. RESULTS IL-22 levels in serum significantly differed among control women and patients with pre-POI and POI, with the lowest concentrations in POI group (p = .019). Significant reduction of peripheral CD4+ IL-22+ T cells was observed in patients with POI (p = .010), which mainly contributed by decrease of CD4+ IL-22+ IL-17- TH 22 cells (p = .012) but not TH 17 cells (p = .125). Levels of serum IL-22 and IL-22-producing CD4+ T subsets were significantly correlated with ovarian reserve markers, including AMH, bilateral AFC, follicle-stimulating hormone (FSH), and E2 (p < .05). The specific receptor IL22RA1 expression was marginally reduced in granulosa cells from patients with pre-POI (p = .051). No difference of IL-22BP was observed either in serum (p = .216) or follicular fluid (p = .856) among groups. CONCLUSIONS Our study first demonstrated the significant association between TH 22-mediated IL-22 deficiency and ovarian insufficiency, which provide new insights into the autoimmune disturbance and opens new avenues for exogenous IL-22 administration as potential intervention of POI.
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Affiliation(s)
- Wenzhe Zhang
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Shiru Xu
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Rongrong Zhang
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Zhuqing Li
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Nianyu Li
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Xiruo Zhang
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Yueshuang Lu
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Yuehong Bian
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Ping Yang
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Fang Fang
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Yingying Qin
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Xue Jiao
- Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
- Suzhou Research Institute, Shandong University, Suzhou, Jiangsu, China
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Zhang L, Ma X, Shi R, Zhang L, Zhao R, Duan R, Qin Y, Gao S, Li X, Duan J, Li J. Allicin ameliorates imiquimod-induced psoriasis-like skin inflammation via disturbing the interaction of keratinocytes with IL-17A. Br J Pharmacol 2023; 180:628-646. [PMID: 36355777 DOI: 10.1111/bph.15983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 09/13/2022] [Accepted: 10/20/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Psoriasis is an inflammatory skin disease of chronic recurrence mediated by the interaction between IL-17 and keratinocytes, which sustains a vicious circle of inflammation. Safe and effective natural medicine is a potential strategy for the clinical treatment of psoriasis. Given its prominent anti-proliferative and anti-inflammatory properties, we investigated the actions of allicin in improving psoriasis. EXPERIMENTAL APPROACH Pharmacodynamic studies were carried out in mice after topical administration of allicin against psoriasis-like lesions induced by imiquimod. Skin sensitization tests were evaluated on guinea pigs. Toxicological studies and skin irritation tests were assessed by consecutive topical allicin alone on the skin of rabbits. RNA-seq probed transcriptomic changes following allicin. Western blot explored the actions of allicin on the interaction between IL-17A and keratinocytes. Changes in inflammatory factor expression were analysed by qPCR and immunohistochemistry. KEY RESULTS Allicin significantly improved the epidermal structure by inhibiting the excessive proliferation and reduced apoptosis of keratinocytes. Furthermore, allicin reduced the secretion of inflammatory cytokines (IL-17A/F, IL-22, IL-12, and IL-20), chemokines (CXCL2, CXCL5, and CCL20), and anti-bacterial peptides (S100a8/9). Mechanistically, allicin directly inhibited the IL-17-induced TRAF6/MAPK/NF-κB and STAT3/NF-κB signalling cascades in keratinocytes, thus breaking the positive inflammatory feedback and alleviating imiquimod-induced psoriasis-like dermatitis in mice. Importantly, topical administration of allicin did not cause skin allergy, and the safety and adaptability of long-term application were verified. CONCLUSIONS AND IMPLICATIONS Interfering with IL-17 signalling in keratinocytes with allicin is a promising strategy for treating psoriasis, given its safety and effectiveness.
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Affiliation(s)
- Lu Zhang
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Xuehong Ma
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Rongmei Shi
- College of Pharmacy, Xinjiang Medical University, Urumqi, China.,Key Laboratory of Garlic Medicinal Research in Xinjiang, Urumqi, China
| | - Libo Zhang
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ruolin Zhao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ran Duan
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yuanyuan Qin
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Sijia Gao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Xinxia Li
- College of Pharmacy, Xinjiang Medical University, Urumqi, China.,Key Laboratory of Garlic Medicinal Research in Xinjiang, Urumqi, China
| | - Jingjing Duan
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jianguang Li
- Xinjiang University of Science and Technology, Korla, China
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Lopez BS. Can Infectious Disease Control Be Achieved without Antibiotics by Exploiting Mechanisms of Disease Tolerance? Immunohorizons 2022; 6:730-740. [DOI: 10.4049/immunohorizons.2200043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/04/2022] [Indexed: 01/04/2023] Open
Abstract
Abstract
Antimicrobial use in animal agriculture may be contributing to the emerging public health crisis of antimicrobial resistance. The sustained prevalence of infectious diseases driving antimicrobial use industry-wide suggests that traditional methods of bolstering disease resistance are, for some diseases, ineffective. A paradigm shift in our approach to infectious disease control is needed to reduce antimicrobial use and sustain animal and human health and the global economy. Targeting the defensive mechanisms that promote the health of an infected host without impacting pathogen fitness, termed “disease tolerance,” is a novel disease control approach ripe for discovery. This article presents examples of disease tolerance dictating clinical outcomes for several infectious diseases in humans, reveals evidence suggesting a similarly critical role of disease tolerance in the progression of infectious diseases plaguing animal agriculture, and thus substantiates the assertion that exploiting disease tolerance mechanisms can positively impact animal and human health.
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Affiliation(s)
- Brina S. Lopez
- Department of Farm Animal Medicine, Midwestern University College of Veterinary Medicine, Glendale, AZ
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15
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3'mRNA sequencing reveals pro-regenerative properties of c5ar1 during resolution of murine acetaminophen-induced liver injury. NPJ Regen Med 2022; 7:10. [PMID: 35087052 PMCID: PMC8795215 DOI: 10.1038/s41536-022-00206-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 12/20/2021] [Indexed: 12/16/2022] Open
Abstract
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
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16
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Barman TK, Metzger DW. Disease Tolerance during Viral-Bacterial Co-Infections. Viruses 2021; 13:v13122362. [PMID: 34960631 PMCID: PMC8706933 DOI: 10.3390/v13122362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/29/2021] [Accepted: 11/23/2021] [Indexed: 11/16/2022] Open
Abstract
Disease tolerance has emerged as an alternative way, in addition to host resistance, to survive viral-bacterial co-infections. Disease tolerance plays an important role not in reducing pathogen burden, but in maintaining tissue integrity and controlling organ damage. A common co-infection is the synergy observed between influenza virus and Streptococcus pneumoniae that results in superinfection and lethality. Several host cytokines and cells have shown promise in promoting tissue protection and damage control while others induce severe immunopathology leading to high levels of morbidity and mortality. The focus of this review is to describe the host cytokines and innate immune cells that mediate disease tolerance and lead to a return to host homeostasis and ultimately, survival during viral-bacterial co-infection.
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Stülb H, Bachmann M, Gonther S, Mühl H. Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product. Int J Mol Sci 2021; 22:10623. [PMID: 34638962 PMCID: PMC8509061 DOI: 10.3390/ijms221910623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 12/13/2022] Open
Abstract
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
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Affiliation(s)
| | | | | | - Heiko Mühl
- Pharmazentrum Frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Faculty of Medicine, Goethe-University Frankfurt, D-60590 Frankfurt am Main, Germany; (H.S.); (M.B.); (S.G.)
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Luo JW, Hu Y, Liu J, Yang H, Huang P. Interleukin-22: a potential therapeutic target in atherosclerosis. Mol Med 2021; 27:88. [PMID: 34388961 PMCID: PMC8362238 DOI: 10.1186/s10020-021-00353-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/07/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Atherosclerosis is recognized as a chronic immuno-inflammatory disease that is characterized by the accumulation of immune cells and lipids in the vascular wall. In this review, we focus on the latest advance regarding the regulation and signaling pathways of IL-22 and highlight its impacts on atherosclerosis. MAIN BODY IL-22, an important member of the IL-10 family of cytokines, is released by cells of the adaptive and innate immune system and plays a key role in the development of inflammatory diseases. The binding of IL-22 to its receptor complex can trigger a diverse array of downstream signaling pathways, in particular the JAK/STAT, to induce the expression of chemokines and proinflammatory cytokines. Recently, numerous studies suggest that IL-22 is involved in the pathogenesis of atherosclerosis by regulation of VSMC proliferation and migration, angiogenesis, inflammatory response, hypertension, and cholesterol metabolism. CONCLUSION IL-22 promotes the development of atherosclerosis by multiple mechanisms, which may be a promising therapeutic target in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Jin-Wen Luo
- Department of Cardio-Thoracic Surgery, Hunan Children's Hospital, Changsha, 410007, People's Republic of China
| | - Yuan Hu
- Department of Ultrasound Medicine, Hunan Children's Hospital, Changsha, 410007, People's Republic of China
| | - Jian Liu
- Department of Cardio-Thoracic Surgery, Hunan Children's Hospital, Changsha, 410007, People's Republic of China
| | - Huan Yang
- Department of Respiratory Medicine, Hunan Provincial People's Hospital, Changsha, Hunan, 410001, People's Republic of China.
| | - Peng Huang
- Department of Cardio-Thoracic Surgery, Hunan Children's Hospital, Changsha, 410007, People's Republic of China.
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19
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Rae J, Hackney J, Huang K, Keir M, Herman A. Identification of an IL-22-Dependent Gene Signature as a Pharmacodynamic Biomarker. Int J Mol Sci 2021; 22:8205. [PMID: 34360971 PMCID: PMC8347589 DOI: 10.3390/ijms22158205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 11/16/2022] Open
Abstract
Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1β. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1β suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22.
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Affiliation(s)
- Julie Rae
- OMNI Biomarker Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA;
| | - Jason Hackney
- Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA; (J.H.); (K.H.)
| | - Kevin Huang
- Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA; (J.H.); (K.H.)
| | - Mary Keir
- OMNI Biomarker Discovery, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA;
| | - Ann Herman
- OMNI Biomarker Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA;
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20
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Zhang Y, Zhou J, Wei Z, Dong H, Yang D, Deng Y, Li J, Shi S, Sun Y, Lu H, Yuan J, Ni B, Wu Y, Tian Y, Han C. TTP-mediated regulation of mRNA stability in immune cells contributes to adaptive immunity, immune tolerance and clinical applications. RNA Biol 2021; 18:2150-2156. [PMID: 33866923 DOI: 10.1080/15476286.2021.1917185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Dendritic cells (DCs) form a sentinel network to induce protective immunity against pathogens or self-tolerance. mRNA stability is an important part of the post-transcriptional regulation (PTR) that controls the maturation and function of DCs. In this review, we summarize the effects of TTP-mediated regulation of mRNA stability in DCs, focusing on DC maturation and antigen presentation, T cell activation and differentiation, immune tolerance and inflammation. We also discuss the potential DC-based immune treatment for HIV+ patients through regulation of mRNA stability. This review proposes the regulation of mRNA stability as a novel immune therapy for various inflammatory diseases, such as arthritis and dermatitis.
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Affiliation(s)
- Yiwei Zhang
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Jian Zhou
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Zhiyuan Wei
- Department of Orthopedics, The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Hui Dong
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Di Yang
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Yuanyu Deng
- School of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Jiahui Li
- School of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Saiyu Shi
- School of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Yi Sun
- The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Huimin Lu
- The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Jizhao Yuan
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Bing Ni
- Department of Pathophysiology, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China.,Department of Orthopedics, The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Yi Tian
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China.,School of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing, PR China
| | - Chao Han
- Institute of Immunology, PLA, Third Military Medical University (Army Medical University), Chongqing, PR China
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21
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Su SB, Qin SY, Xian XL, Huang FF, Huang QL, ZhangDi HJ, Jiang HX. Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis. Life Sci 2021; 264:118677. [PMID: 33129875 DOI: 10.1016/j.lfs.2020.118677] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/14/2020] [Accepted: 10/24/2020] [Indexed: 12/19/2022]
Abstract
AIMS Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M1 (pro-inflammatory) and M2 (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis. MAIN METHODS Utilized CCl4 to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/Erk/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis. KEY FINDINGS During CCl4-induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M1-KCs, and it increased the number of M2-KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M2/M1-KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M2-KCs to M1-KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M1 to M2. The cytokine exerted these effects by activating the STAT3 pathway while suppressing Erk1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M2-KCs during liver fibrogenesis. SIGNIFICANCE IL-22 regulates the STAT3/Erk/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.
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Affiliation(s)
- Si-Biao Su
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Shan-Yu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Xiao-Long Xian
- Graduate School of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Fei-Fei Huang
- Graduate School of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Qiu-Lan Huang
- Graduate School of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Han-Jing ZhangDi
- Graduate School of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Hai-Xing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China.
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22
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Li S, Qin Q, Luo D, Pan W, Wei Y, Xu Y, Wang J, Ye X, Zhu J, Shang L. IL-17 is a potential biomarker for predicting the severity and outcomes of pulmonary contusion in trauma patients. Biomed Rep 2020; 14:5. [PMID: 33235720 PMCID: PMC7678624 DOI: 10.3892/br.2020.1381] [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: 08/14/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022] Open
Abstract
Pulmonary contusion (PC) is very common in blunt chest trauma, and always results in negative pulmonary outcomes, such as pneumonia, acute respiratory distress syndrome (ARDS), respiratory failure or even death. However, there are no effective biomarkers which can be used to predict the outcomes in these patients. The present study aimed to determine the value of interleukin (IL)-17 and IL-22 in predicting the severity and outcomes of PC in trauma patients. All trauma patients admitted to The First Affiliated Hospital of Guangxi Medical University between January 2015 and December 2017, were studied. Patients aged >14 years old with a diagnosis of PC upon their admission to the emergency department were included. Patients with PC were enrolled as the PC group, patients without PC were enrolled as the non-PC group, and healthy individuals were selected as the control group. Clinical information, including sociodemographic parameters, clinical data, biological findings and therapeutic interventions were recorded for all patients who were enrolled. Blood samples were collected and stored according to the established protocols. PC volume was measured by computed tomography and plasma cytokine levels were assayed by ELISA. A total of 151 patients with PC (PC group) and 159 patients without PC (non-PC group) were included in the present study. In addition, 50 healthy individuals were used as the control group. The primary cause of PC was motor vehicle crashes. PC patients had more rib fractures, but similar injury severity scores compared with other patients. More patients received Pleurocan drainage treatment and had pneumonia complications in the PC group compared with the other two groups. PC patients had a high incidence of ARDS and admission to the intensive care unit (ICU). PC patients also experienced longer periods on mechanical ventilation and had longer stays in the ICU and hospital. PC volume was effective in predicting the outcomes of PC patients. IL-22 levels were similar in the PC group and non-PC group. However, IL-17 could be used as a biomarker to predict the severity of PC, and was strongly associated with PC volume. IL-17 was significantly associated with pro-inflammatory complications in PC patients and could be used as a biomarker for predicting in-patient outcomes of patients with PC. In conclusion, IL-17 is a potential biomarker for predicting the severity and outcomes of PC in trauma patients.
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Affiliation(s)
- Shilai Li
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Quanlin Qin
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Daqing Luo
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Wenhui Pan
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yuqing Wei
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yansong Xu
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Junxuan Wang
- Department of Medical Records, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jijin Zhu
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Liming Shang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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23
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Arshad T, Mansur F, Palek R, Manzoor S, Liska V. A Double Edged Sword Role of Interleukin-22 in Wound Healing and Tissue Regeneration. Front Immunol 2020; 11:2148. [PMID: 33042126 PMCID: PMC7527413 DOI: 10.3389/fimmu.2020.02148] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/07/2020] [Indexed: 12/14/2022] Open
Abstract
Wound healing and tissue regeneration is an intricate biological process that involves repair of cellular damage and maintenance of tissue integrity. Cascades involved in wound healing and tissue regeneration highly overlap with cancer causing pathways. Usually, subsequent tissue damage events include release of a number of cytokines to accomplish post-trauma restoration. IL-22 is one of the cytokines that are immediately produced to initiate immune response against several tissue impairments. IL-22 is a fundamental mediator in inflammation, mucous production, protective role against pathogens, wound healing, and tissue regeneration. However, accumulating evidence suggests pivotal role of IL-22 in instigation of various cancers due to its pro-inflammatory and tissue repairing activity. In this review, we summarize how healing effects of IL-22, when executed in an uncontrollable fashion can lead to carcinogenesis.
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Affiliation(s)
- Tanzeela Arshad
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Fizzah Mansur
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Richard Palek
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Sobia Manzoor
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Vaclav Liska
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
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24
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The Construction and Immunoadjuvant Activities of the Oral Interleukin-17B Expressed by Lactobacillus plantarum NC8 Strain in the Infectious Bronchitis Virus Vaccination of Chickens. Vaccines (Basel) 2020; 8:vaccines8020282. [PMID: 32517220 PMCID: PMC7350006 DOI: 10.3390/vaccines8020282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
Interleukin-17B (IL-17B) is a protective cytokine of the IL-17 family and plays an essential role in the regulation of mucosal inflammation. However, little is known about the role of IL-17B in the control of viral infections. In this study, a recombinant Lactobacillus plantarum, designated as NC8-ChIL17B, was constructed to express the chicken IL-17B (ChIL-17B) gene. The recombinant ChIL17B (rChIL17B) protein was about 14 kDa and was anchored to the surface of NC8 cells. In vitro, it was found that the rChIL17B protein inhibited the proliferation of the infectious bronchitis virus (IBV) through activation of nuclear factor kappa B (NF-κB) and the JAK (Janus kinase)-STAT (signal transducers and activators of transcription) signaling. Moreover, to evaluate the immunoadjuvant activities of NC8-ChIL17B, 40 three-day-old specific pathogen-free (SPF) chickens were divided into four groups. Three groups were orally vaccinated with fresh NC8, NC8-ChIL17B, and phosphate buffered saline (PBS), along with the infectious bronchitis virus vaccine, and the other group was the PBS-negative control. The results of the IBV-specific antibody titer and the concentration of the cytokines IL-2, IL-4, IL-6, and interferon gamma (IFN-γ) in sera, as well as the concentration of secretory immunoglobulin A (sIgA) in the tracheal and small intestinal mucosa, the number of cluster of differentiation 4 positive (CD4+) and cluster of differentiation 8 positive (CD8+) T cells in the blood, and the expression of immune-related genes all indicated that NC8-ChIL17B efficiently enhanced the humoral and cellular immune responses to IBV vaccine. Moreover, the viral loads in the NC8-ChIL17B- and IBV-vaccinated group were significantly lower than in the control groups, suggesting a significant promotion of the immunoprotection of IBV vaccination against the virulent IBV strain. Therefore, ChIL-17B is a promising, effective adjuvant candidate for chicken virus vaccines.
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25
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Takahashi J, Yamamoto M, Yasukawa H, Nohara S, Nagata T, Shimozono K, Yanai T, Sasaki T, Okabe K, Shibata T, Mawatari K, Kakuma T, Aoki H, Fukumoto Y. Interleukin-22 Directly Activates Myocardial STAT3 (Signal Transducer and Activator of Transcription-3) Signaling Pathway and Prevents Myocardial Ischemia Reperfusion Injury. J Am Heart Assoc 2020; 9:e014814. [PMID: 32301368 PMCID: PMC7428538 DOI: 10.1161/jaha.119.014814] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Interleukin (IL)-22, a member of the IL-10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL-22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription-3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS We evaluated the STAT3 activation after IL-22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL-22 injection. Coimmunostaining of phosphorylated STAT3 and α-actinin revealed that STAT3 activation occurred in cardiomyocytes after IL-22 administration. In heart tissue from intact mice, real-time PCR demonstrated significant expression of IL-22 receptor subunit 1, and coimmunostaining of IL-22 receptor subunit 1 and α-actinin showed IL-22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL-22 activated STAT3, and we detected IL-22 receptor subunit 1 expression. Overall, these results indicated that IL-22 directly activated the myocardial IL-22-receptor subunit 1-STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS-treated mice, IL-22-treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL-22-treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS Our present findings suggest that IL-22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.
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Affiliation(s)
- Jinya Takahashi
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Mai Yamamoto
- Cardiovascular Research InstituteKurume UniversityKurumeJapan
| | - Hideo Yasukawa
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Shoichiro Nohara
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Takanobu Nagata
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Koutatsu Shimozono
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Toshiyuki Yanai
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Tomoko Sasaki
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Kota Okabe
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Tatsuhiro Shibata
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | - Kazutoshi Mawatari
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
| | | | - Hiroki Aoki
- Cardiovascular Research InstituteKurume UniversityKurumeJapan
| | - Yoshihiro Fukumoto
- Division of Cardiovascular MedicineDepartment of Internal MedicineKurume University School of MedicineKurumeJapan
- Cardiovascular Research InstituteKurume UniversityKurumeJapan
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26
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Rudloff I, Jardé T, Bachmann M, Elgass KD, Kerr G, Engel R, Richards E, Oliva K, Wilkins S, McMurrick PJ, Abud HE, Mühl H, Nold MF. Molecular signature of interleukin-22 in colon carcinoma cells and organoid models. Transl Res 2020; 216:1-22. [PMID: 31734267 DOI: 10.1016/j.trsl.2019.10.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 10/18/2019] [Accepted: 10/22/2019] [Indexed: 12/18/2022]
Abstract
Interleukin (IL)-22 activates STAT (signal transducer and activator of transcription) 3 and antiapoptotic and proproliferative pathways; but beyond this, the molecular mechanisms by which IL-22 promotes carcinogenesis are poorly understood. Characterizing the molecular signature of IL-22 in human DLD-1 colon carcinoma cells, we observed increased expression of 26 genes, including NNMT (nicotinamide N-methyltransferase, ≤10-fold) and CEA (carcinoembryonic antigen, ≤7-fold), both known to promote intestinal carcinogenesis. ERP27 (endoplasmic reticulum protein-27, function unknown, ≤5-fold) and the proinflammatory ICAM1 (intercellular adhesion molecule-1, ≤4-fold) were also increased. The effect on CEA was partly STAT3-mediated, as STAT3-silencing reduced IL-22-induced CEA by ≤56%. Silencing of CEA or NNMT inhibited IL-22-induced proliferation/migration of DLD-1, Caco-2, and SW480 colon carcinoma cells. To validate these results in primary tissues, we assessed IL-22-induced gene expression in organoids from human healthy colon and colon cancer patients, and from normal mouse small intestine and colon. Gene regulation by IL-22 was similar in DLD-1 cells and human and mouse healthy organoids. CEA was an exception with no induction by IL-22 in organoids, indicating the 3-dimensional organization of the tissue may produce signals absent in 2D cell culture. Importantly, augmentation of NNMT was 5-14-fold greater in human cancerous compared to normal organoids, supporting a role for NNMT in IL-22-mediated colon carcinogenesis. Thus, NNMT and CEA emerge as mediators of the tumor-promoting effects of IL-22 in the intestine. These data advance our understanding of the multifaceted role of IL-22 in the gut and suggest the IL-22 pathway may represent a therapeutic target in colon cancer.
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Affiliation(s)
- Ina Rudloff
- Department of Paediatrics, Monash University, Clayton, Melbourne, Australia; Ritchie Centre, Hudson Institute of Medical Research, Clayton, Melbourne, Australia; Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Frankfurt am Main, Germany.
| | - Thierry Jardé
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Australia; Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Melbourne, Australia
| | - Malte Bachmann
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Kirstin D Elgass
- Monash Micro Imaging, Hudson Institute of Medical Research, Clayton, Melbourne, Australia
| | - Genevieve Kerr
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Australia; Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Australia
| | - Rebekah Engel
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Australia; Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Australia; Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, Melbourne, Australia
| | - Elizabeth Richards
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Australia; Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Australia
| | - Karen Oliva
- Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, Melbourne, Australia
| | - Simon Wilkins
- Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Paul J McMurrick
- Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, Melbourne, Australia
| | - Helen E Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Australia; Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Australia
| | - Heiko Mühl
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Marcel F Nold
- Department of Paediatrics, Monash University, Clayton, Melbourne, Australia; Ritchie Centre, Hudson Institute of Medical Research, Clayton, Melbourne, Australia.
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27
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Tripathi D, Radhakrishnan RK, Sivangala Thandi R, Paidipally P, Devalraju KP, Neela VSK, McAllister MK, Samten B, Valluri VL, Vankayalapati R. IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis. PLoS Pathog 2019; 15:e1008140. [PMID: 31809521 PMCID: PMC6919622 DOI: 10.1371/journal.ppat.1008140] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 12/18/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022] Open
Abstract
Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.
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Affiliation(s)
- Deepak Tripathi
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Rajesh Kumar Radhakrishnan
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Ramya Sivangala Thandi
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Kamakshi Prudhula Devalraju
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Venkata Sanjeev Kumar Neela
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Madeline Kay McAllister
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Buka Samten
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Vijaya Lakshmi Valluri
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
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Molina MF, Abdelnabi MN, Fabre T, Shoukry NH. Type 3 cytokines in liver fibrosis and liver cancer. Cytokine 2019; 124:154497. [PMID: 30097286 DOI: 10.1016/j.cyto.2018.07.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/23/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
The type 3 cytokines IL-17 and IL-22 play a crucial, well synchronized physiological role in wound healing and repairing tissue damage due to infections or injury at barrier surfaces. These cytokines act on epithelial cells to induce secretion of early immune mediators, recruitment of inflammatory cells to the site of injury, and to trigger tissue repair mechanisms. However, if the damage persists or if these cytokines are dysregulated, then they contribute to a number of inflammatory pathologies, autoimmune conditions and cancer. The liver is a multifunctional organ that plays an essential role in metabolism, detoxification, and immune surveillance. It is also exposed to a variety of pathogens, toxins and injuries. Over the past decade, IL-17 and IL-22 have been implicated in various aspects of liver inflammation. IL-17 is upregulated in chronic liver injury and associated with liver disease progression. In contrast, IL-22 was shown to be hepatoprotective during acute liver injury but exhibited inflammatory effects in other models. Furthermore, IL-22 and IL-17 are both associated with poor prognosis in liver cancer. Finally, the regulatory mechanisms governing the physiological versus the pathological role of these two cytokines during acute and chronic liver injury remain poorly understood. In this review, we will summarize the current state of knowledge about IL-17 and IL-22 in wound healing during acute and chronic liver injury, their contribution to pathogenesis, their regulation, and their role in the transition from advanced liver disease to liver cancer.
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Affiliation(s)
- Manuel Flores Molina
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Mohamed N Abdelnabi
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Thomas Fabre
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
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29
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Tahrali I, Kucuksezer UC, Akdeniz N, Altintas A, Uygunoglu U, Aktas-Cetin E, Deniz G. CD3 -CD56 + NK cells display an inflammatory profile in RR-MS patients. Immunol Lett 2019; 216:63-69. [PMID: 31589897 DOI: 10.1016/j.imlet.2019.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/22/2019] [Accepted: 10/03/2019] [Indexed: 01/06/2023]
Abstract
Multiple Sclerosis (MS) is an immune-mediated and neurodegenerative disease of central nervous system. Relapsing-remitting (RR)-MS occurring with acute attacks and remissions, is the most common clinical type of MS. There are different strategies applied in first-line treatment of RR-MS patients such as interferon-beta (IFN-β) and glatiramer acetate. In this study, activating and inhibitory receptor expressions and interleukin (IL)-22 levels of NK cells were investigated in RR-MS patients with or without IFN-β therapy. Activating receptor expression and IL-22 levels of NK cells were increased in RR-MS patients under IFN-β therapy. Elevated NK cells with activating profile and increased IL-22 under IFN-β therapy suggest that IFN-β treatment might direct NK cells toward a pro-inflammatory status.
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Affiliation(s)
- Ilhan Tahrali
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey
| | - Umut Can Kucuksezer
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey
| | - Nilgun Akdeniz
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey
| | - Ayse Altintas
- Koc University, Faculty of Medicine, Department of Neurology, Istanbul, Turkey; Istanbul University Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Neurology, Istanbul, Turkey
| | - Ugur Uygunoglu
- Istanbul University Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Neurology, Istanbul, Turkey
| | - Esin Aktas-Cetin
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey
| | - Gunnur Deniz
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey.
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30
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Mühl H, Bachmann M. IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential. Cell Signal 2019; 63:109388. [PMID: 31401146 DOI: 10.1016/j.cellsig.2019.109388] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023]
Abstract
Interleukin (IL)-18 and IL-22 are key components of cytokine networks that play a decisive role in (pathological) inflammation, host defense, and tissue regeneration. Tight regulation of cytokine-driven signaling, inflammation, and immunoactivation is supposed to enable nullification of a given deleterious trigger without mediating overwhelming collateral tissue damage or even activating a cancerous face of regeneration. In fact, feedback regulation by specific cytokine opponents is regarded as a major means by which the immune system is kept in balance. Herein, we shine a light on the interplay between IL-18 and IL-22 and their opponents IL-18 binding protein (IL-18BP) and IL-22BP in order to provide integrated information on their biology, pathophysiological significance, and prospect as targets and/or instruments of therapeutic intervention.
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Affiliation(s)
- Heiko Mühl
- pharmazentrum frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Theodor-Stern- Kai 7, 60590 Frankfurt am Main, Germany.
| | - Malte Bachmann
- pharmazentrum frankfurt/ZAFES, University Hospital Goethe University Frankfurt am Main, Theodor-Stern- Kai 7, 60590 Frankfurt am Main, Germany
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31
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Zhuang Gu Guan Jie Wan: Reasonable Application Can Alleviate the Liver Injury for Osteoarthritis Treatment. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:6716529. [PMID: 30538762 PMCID: PMC6260402 DOI: 10.1155/2018/6716529] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 09/23/2018] [Accepted: 10/25/2018] [Indexed: 12/20/2022]
Abstract
The potential toxicity of herbal drugs, particularly drug-induced liver injury (DILI), has received extensive attention as the use of Chinese herbal medicine has rapidly increased globally. As a classic Chinese patent medicine, Zhuang Gu Guan Jie Wan (ZGGJW) has been brought into focus recently because of its satisfactory therapeutic effects on osteoarthritis (OA) as well as its unanticipated side effects. This study aimed to decipher the puzzling phenomenon of liver injury developing in response to ZGGJW that varies by the subtype of OA. Normal, anterior cruciate ligament transaction (ACLT) and partial medial meniscectomy (MMx) induced OA and ovariectomy combined with ACLT and partial MMx induced rat models were used and treated orally with ZGGJW or distilled water for 30 days. The results from histopathology, biochemistry, and immunohistochemistry showed that ZGGJW induced liver injury, increased the level of malondialdehyde (MDA), and decreased the levels of total antioxidation capability (T-AOC), superoxide dismutase (SOD), interleukin-22 (IL-22), and signal transducer and activator of transcription factor 3 (STAT3) in the liver of normal rats, while liver injury was alleviated and showed different tendencies in the above markers for ACLT and partial MMx induction rats and ovariectomy combined with ACLT and partial MMx induction rats after ZGGJW treatment. In the OA disease states, hepatic injury induced by ZGGJW could be associated with an impairment in antioxidant capacity and the high levels of IL-22 and STAT3 after ZGGJW treatment may be responsible for the slight hepatic injury of ZGGJW based on the subtype of OA. This study provides a novel approach to better understanding of the risks and limitations when using potentially toxic Chinese patent medicine in clinical applications.
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32
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Zheng Y, Li T. Interleukin-22, a potent target for treatment of non-autoimmune diseases. Hum Vaccin Immunother 2018; 14:2811-2819. [PMID: 30335564 DOI: 10.1080/21645515.2018.1509649] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Interleukin -22 (IL-22) is a member of interleukin-10 (IL-10) family cytokines that is produced by different types of lymphocytes included in both innate and adaptive immune systems. These lymphocytes include activated T cells, most notably Th17 and Th22 cells, as well as NK cells, γδ T cells, etc. IL-22 mediate its effects via the IL-22-IL-22R complex and subsequent Janus Kinase-signal transduces and activators transcription (JAK-STAT) signaling pathway. According to recent evidence, IL-22 played a critical role in the pathogenesis of many non-autoimmune diseases. In this review, we mainly discussed the recent findings and advancements of the role of IL-22 in several non-autoimmune diseases, such as acute lung injury, atherosclerosis and some bacterial infections, suggesting that IL-22 may have therapeutic potential for treating non-autoimmune diseases.
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Affiliation(s)
- Yue Zheng
- a Cardiology , The Third Central Clinical College of Tianjin Medical University , Tianjin , China.,b Cardiology , Tianjin Key Laboratory of Artificial Cell.,c Artificial Cell Engineering Technology Research Center of Public Health Ministry , Tianjin , China.,d Tianjin Institute of Hepatobiliary Disease , Tianjin , China
| | - Tong Li
- b Cardiology , Tianjin Key Laboratory of Artificial Cell.,c Artificial Cell Engineering Technology Research Center of Public Health Ministry , Tianjin , China.,d Tianjin Institute of Hepatobiliary Disease , Tianjin , China.,e The Third Central Hospital of Tianjin , Tianjin , China
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33
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Zhou H, Xie G, Mao Y, Zhou K, Ren R, Zhao Q, Wang H, Yin S. Enhanced Regeneration and Hepatoprotective Effects of Interleukin 22 Fusion Protein on a Predamaged Liver Undergoing Partial Hepatectomy. J Immunol Res 2018; 2018:5241526. [PMID: 30515423 PMCID: PMC6234454 DOI: 10.1155/2018/5241526] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/29/2018] [Indexed: 02/06/2023] Open
Abstract
Liver ischemia-reperfusion injury (IRI) and regeneration deficiency are two major challenges for surgery patients with chronic liver disease. As a survival factor for hepatocytes, interleukin 22 (IL-22) plays an important role in hepatoprotection and the promotion of regeneration after hepatectomy. In this study, we aim to investigate the roles of an interleukin 22 fusion protein (IL-22-FP) in mice with a predamaged liver after a two-third partial hepatectomy (PHx). Predamaged livers in mice were induced by concanavalin A (ConA)/carbon tetrachloride (CCl4) following PHx with or without IL-22-FP treatment. A hepatic IRI mouse model was also used to determine the hepatoprotective effects of IL-22-FP. In the ConA/CCl4 model, IL-22-FP treatment alleviated liver injury and accelerated hepatocyte proliferation. Administration of IL-22-FP activated the hepatic signal transducer and activator of transcription 3 (STAT3) and upregulated the expression of many mitogenic proteins. IL-22-FP treatment prior to IRI effectively reduced liver damage through decreased aminotransferase and improved liver histology. In conclusion, IL-22-FP promotes liver regeneration in mice with predamaged livers following PHx and alleviates IRI-induced liver injury. Our study suggests that IL-22-FP may represent a promising therapeutic drug against regeneration deficiency and liver IRI in patients who have undergone PHx.
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Affiliation(s)
- Heng Zhou
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
| | - Guomin Xie
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
| | - Yudi Mao
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
| | - Ke Zhou
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
| | - Ruixue Ren
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Qihong Zhao
- Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Hua Wang
- Institute for Liver Disease, Anhui Medical University, Hefei 230032, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Shi Yin
- Department of Geriatrics, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China
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34
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Yu L, Wang F, Cui Y, Li D, Yao W, Yang G. Molecular characteristics of rhesus macaque interleukin-22: cloning, in vitro expression and biological activities. Immunology 2018; 154:651-662. [PMID: 29465767 PMCID: PMC6050205 DOI: 10.1111/imm.12914] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 02/12/2018] [Accepted: 02/14/2018] [Indexed: 12/19/2022] Open
Abstract
Interleukin-22 (IL-22) is a potential therapeutic agent for diseases driven by epithelial injury. To characterize the IL-22 expressed by rhesus macaques, animals that are irreplaceable for human disease research, rhesus macaque IL-22 (rhIL-22) was cloned and expressed, and its biological activity and in vivo distribution were examined. It was found that the rhIL-22 gene consists of five introns and six exons, including a short non-coding exon starting 22 bp downstream of a putative TATA box. The amino acid sequence of rhIL-22 showed 95·5% identity to that of humans, and it shared two conserved disulphide bonds, three N-glycosylation sites and all the critical residues for binding to IL-22R1. High levels of IL-22 mRNA were observed in the liver, pancreas, lymphoid tissues and especially in the outer-body barriers such as the intestinal tract of rhesus macaques. Functionally, purified rhIL-22 has a similar but a little earlier effect on signal transducer and activator of transcription 3 phosphorylation at Tyr705 compared with that of commercial human IL-22. The expression of the antibacterial proteins β-defensin-2, S100A8, S100A9, RegIIIα and Muc1 by HT-29 cells was largely upregulated after stimulation with rhIL-22. Recombinant rhIL-22 could also significantly promote the proliferation of human intestinal epithelial cells without affecting cell apoptosis. These data indicate that rhesus macaque IL-22 is highly similar to that of humans in both structure and function, and tests of therapeutic effects of human IL-22 on human diseases in rhesus macaques are warranted.
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Affiliation(s)
- Lei Yu
- National Centre for AIDS/STD Control and Prevention, China CDCBeijingChina
| | - Feng‐Jie Wang
- National Centre for AIDS/STD Control and Prevention, China CDCBeijingChina
| | - Yan‐Fang Cui
- National Centre for AIDS/STD Control and Prevention, China CDCBeijingChina
| | - Dong Li
- National Centre for AIDS/STD Control and Prevention, China CDCBeijingChina
| | - Wen‐Rong Yao
- National Centre for AIDS/STD Control and Prevention, China CDCBeijingChina
| | - Gui‐Bo Yang
- National Centre for AIDS/STD Control and Prevention, China CDCBeijingChina
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35
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Barthelemy A, Sencio V, Soulard D, Deruyter L, Faveeuw C, Le Goffic R, Trottein F. Interleukin-22 Immunotherapy during Severe Influenza Enhances Lung Tissue Integrity and Reduces Secondary Bacterial Systemic Invasion. Infect Immun 2018; 86:e00706-17. [PMID: 29661933 PMCID: PMC6013680 DOI: 10.1128/iai.00706-17] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 04/03/2018] [Indexed: 12/15/2022] Open
Abstract
Severe bacterial (pneumococcal) infections are commonly associated with influenza and are significant contributors to the excess morbidity and mortality of influenza. Disruption of lung tissue integrity during influenza participates in bacterial pulmonary colonization and dissemination out of the lungs. Interleukin-22 (IL-22) has gained considerable interest in anti-inflammatory and anti-infection immunotherapy over the last decade. In the current study, we investigated the effect of exogenous IL-22 delivery on the outcome of pneumococcal superinfection postinfluenza. Our data show that exogenous treatment of influenza virus-infected mice with recombinant IL-22 reduces bacterial dissemination out of the lungs but is without effect on pulmonary bacterial burden. Reduced systemic bacterial dissemination was linked to reinforced pulmonary barrier functions, as revealed by total protein measurement in the bronchoalveolar fluids, intratracheal fluorescein isothiocyanate-dextran tracking, and histological approaches. We describe an IL-22-specific gene signature in the lung tissue of influenza A virus (IAV)-infected (and naive) mice that might explain the observed effects. Indeed, exogenous IL-22 modulates the gene expression profile in a way that suggests reinforcement of tissue integrity. Our results open the way to alternative approaches for limiting postinfluenza bacterial superinfection, particularly, systemic bacterial invasion.
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Affiliation(s)
- Adeline Barthelemy
- Universitaire de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Valentin Sencio
- Universitaire de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Daphnée Soulard
- Universitaire de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Lucie Deruyter
- Universitaire de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Christelle Faveeuw
- Universitaire de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Ronan Le Goffic
- Molecular Virology and Immunology, Institut National de la Recherche Agronomique, Université Paris-Saclay, Jouy-en-Josas, France
| | - François Trottein
- Universitaire de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
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36
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Stefanich EG, Rae J, Sukumaran S, Lutman J, Lekkerkerker A, Ouyang W, Wang X, Lee D, Danilenko DM, Diehl L, Loyet KM, Herman A. Pre-clinical and translational pharmacology of a human interleukin-22 IgG fusion protein for potential treatment of infectious or inflammatory diseases. Biochem Pharmacol 2018; 152:224-235. [PMID: 29608910 DOI: 10.1016/j.bcp.2018.03.031] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 03/28/2018] [Indexed: 01/01/2023]
Abstract
Interleukin (IL)-22 plays protective roles in infections and in inflammatory diseases that have been linked to its meditation of innate immunity via multiple mechanisms. IL-22 binds specifically to its heterodimeric receptor, which is expressed on a variety of epithelial tissues. UTTR1147A is a recombinant fusion protein that links the human cytokine IL-22 with the Fc portion of human immunoglobulin (Ig) G4. Here, we report extensive in vitro and in vivo nonclinical studies that were conducted to characterize the pharmacological activity of UTTR1147A. The in vitro activity and potency of UTTR1147A were analyzed using primary human hepatocytes and human colonic epithelial cell lines. Assessment of in vivo efficacy was performed in a mouse colitis model and by measuring relevant pharmacodynamic biomarkers, including antimicrobial peptides REG3A/β, serum amyloid protein A (SAA) and lipopolysaccharide binding protein (LBP). The pharmacokinetic and pharmacodynamic characteristics of UTTR1147A were assessed in healthy mice, rats and cynomolgus monkeys. UTTR1147A induced STAT3 activation through binding to IL-22 receptor expressed in primary human hepatocytes and human colon cell lines. In both, activation occurred in a concentration-dependent manner with similar potencies. In the mouse colitis model, murine IL-22Fc- (muIL-22Fc) treated groups at doses of 1.25 μg and above had statistically lower average histologic colitis scores compared to the control treated group. Administration of muIL-22Fc or UTTR1147A was associated with a dose-dependent induction of PD markers REG3β and SAA in rodents as well as REG3A, SAA and LBP in cynomolgus monkeys. The combined data confirm pharmacological activity of IL-22Fc and support potential regenerative and protective mechanisms in epithelial tissues.
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Affiliation(s)
| | - Julie Rae
- Genentech, South San Francisco, CA, United States
| | | | - Jeff Lutman
- Genentech, South San Francisco, CA, United States
| | | | | | | | - Donna Lee
- Genentech, South San Francisco, CA, United States
| | | | - Lauri Diehl
- Genentech, South San Francisco, CA, United States
| | | | - Ann Herman
- Genentech, South San Francisco, CA, United States
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37
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Xuan X, Tian Z, Zhang M, Zhou J, Gao W, Zhang Y, Zhang Y, Lei B, Ni B, Wu Y, Fan W. Diverse effects of interleukin-22 on pancreatic diseases. Pancreatology 2018; 18:231-237. [PMID: 29502986 DOI: 10.1016/j.pan.2018.02.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 02/20/2018] [Accepted: 02/23/2018] [Indexed: 12/11/2022]
Abstract
Interleukin-22 (IL-22) is involved in the development of lymphocytes and serves as a rapid and early source of the effector cytokines that are released in response to pathogen-induced changes in the microenvironment. Recent research has implicated IL-22 as a potential contributing factor to the spectrum of inflammation-related pancreatic diseases, particularly pancreatitis, fibrosis, carcinoma and diabetes. In this review, we summarize the current knowledge on the roles of IL-22 in the various pancreatic pathogenesis, providing insights into the underlying cellular and signaling mechanisms that will help guide future research into promising interventional targets with therapeutic potential.
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Affiliation(s)
- Xiuyun Xuan
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China; Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030200, China
| | - Zhiqiang Tian
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China
| | - Mengjie Zhang
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Jian Zhou
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Weiwu Gao
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Yi Zhang
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Yue Zhang
- Department of Dermatology, 105th Hospital of PLA, Bengbu Medical College, Hefei, 230001, China
| | - Bo Lei
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030200, China
| | - Bing Ni
- Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China.
| | - Weiping Fan
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030200, China.
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38
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Curran CS, Bolig T, Torabi-Parizi P. Mechanisms and Targeted Therapies for Pseudomonas aeruginosa Lung Infection. Am J Respir Crit Care Med 2018; 197:708-727. [PMID: 29087211 PMCID: PMC5855068 DOI: 10.1164/rccm.201705-1043so] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 10/26/2017] [Indexed: 12/12/2022] Open
Abstract
Pseudomonas aeruginosa is a complex gram-negative facultative anaerobe replete with a variety of arsenals to activate, modify, and destroy host defense mechanisms. The microbe is a common cause of nosocomial infections and an antibiotic-resistant priority pathogen. In the lung, P. aeruginosa disrupts upper and lower airway homeostasis by damaging the epithelium and evading innate and adaptive immune responses. The biology of these interactions is essential to understand P. aeruginosa pathogenesis. P. aeruginosa interacts directly with host cells via flagella, pili, lipoproteins, lipopolysaccharides, and the type III secretion system localized in the outer membrane. P. aeruginosa quorum-sensing molecules regulate the release of soluble factors that enhance the spread of infection. These characteristics of P. aeruginosa differentially affect lung epithelial, innate, and adaptive immune cells involved in the production of mediators and the recruitment of additional immune cell subsets. Pathogen interactions with individual host cells and in the context of host acute lung infection are discussed to reveal pathways that may be targeted therapeutically.
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Affiliation(s)
- Colleen S Curran
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Thomas Bolig
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Parizad Torabi-Parizi
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland
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Bachmann M, Pfeilschifter J, Mühl H. Epigenetic regulation by CpG methylation splits strong from retarded IFNγ-induced IL-18BP in epithelial versus monocytic cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2018; 1861:191-199. [DOI: 10.1016/j.bbagrm.2018.01.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/19/2018] [Accepted: 01/26/2018] [Indexed: 01/01/2023]
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Lu Z, Liu J, Liu X, Huang E, Yang J, Qian J, Zhang D, Liu R, Chu Y. MicroRNA 15a/16-1 suppresses aryl hydrocarbon receptor-dependent interleukin-22 secretion in CD4 + T cells and contributes to immune-mediated organ injury. Hepatology 2018; 67:1027-1040. [PMID: 29023933 DOI: 10.1002/hep.29573] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/08/2017] [Accepted: 09/27/2017] [Indexed: 12/29/2022]
Abstract
Interleukin-22 (IL-22), as a link between leukocytic and nonleukocytic cells, has gained increasing attention for its pronounced tissue-protective properties. MicroRNAs, emerging as crucial immune modulators, have been reported to be involved in the production and action of various cytokines. However, the precise control of IL-22 by microRNAs and its subsequent actions remained to be elucidated. In this study, we found a negative correlation between the expression of microRNA 15a/16-1 (miR-15a/16-1) and IL-22 in the model of concanavalin A-induced, immune-mediated liver injury. Knockout of miR-15a/16-1 ameliorated liver injury in an IL-22-dependent manner. Further results revealed that cluster of differentiation 4-positive (CD4+ ) T cells were the major source of IL-22 during liver injury and that the aryl hydrocarbon receptor was the direct target of miR-15a/16-1 in CD4+ T cells. In vivo and in vitro data showed that miR-15a/16-1 knockout CD4+ T cells produced more IL-22, while overexpression of miR-15a/16-1 down-regulated the IL-22 production by inhibiting the aryl hydrocarbon receptor. Moreover, transfer of miR-15a/16-1 knockout CD4+ T cells promoted tissue repair compared to wild-type CD4+ T cells by up-regulating IL-22. In addition, as a synergistic effect, IL-22 could down-regulate miR-15a/16-1 expression by activating phosphorylated signal transducer and activator of transcription 3-c-myc signaling, and the decrease of miR-15a/16-1 in damaged hepatocytes contributed to IL-22-mediated tissue repair by reducing cell apoptosis and promoting cell proliferation. As further proof, we demonstrated the role of miR-15a/16-1 in controlling IL-22 production and IL-22-mediated reconstruction of the intestinal epithelial barrier in a dextran sodium sulfate-induced colitis model. CONCLUSION Our results suggest that miR-15a/16-1 acts as a essential regulator of IL-22 and that the miR-15a/16-1-aryl hydrocarbon receptor-IL-22 regulatory axis plays a central role in tissue repair; modulation of miR-15a/16-1 might hold promise in developing new strategies to enhance IL-22-mediated tissue repair. (Hepatology 2018;67:1027-1040).
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Affiliation(s)
- Zhou Lu
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jiajing Liu
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaoming Liu
- Department of Dermatology and Venereology, Shenzhen Hospital, Peking University, Shenzhen, China
| | - Enyu Huang
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jiao Yang
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
- Biotherapy Research Center, Fudan University, Shanghai, China
| | - Jiawen Qian
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
- Biotherapy Research Center, Fudan University, Shanghai, China
| | - Dan Zhang
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
- Biotherapy Research Center, Fudan University, Shanghai, China
| | - Ronghua Liu
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, and Institute of Biomedical Sciences, Fudan University, Shanghai, China
- Biotherapy Research Center, Fudan University, Shanghai, China
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Bachmann M, Pfeilschifter J, Mühl H. A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation. Front Immunol 2018; 9:161. [PMID: 29472923 PMCID: PMC5809456 DOI: 10.3389/fimmu.2018.00161] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 01/18/2018] [Indexed: 12/19/2022] Open
Abstract
Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP)]-induced acute liver injury (ALI) not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL)-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc) to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.
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Affiliation(s)
- Malte Bachmann
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Heiko Mühl
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
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Su SB, Zhang JF, Huang FF, Cen Y, Jiang HX. Large numbers of interleukins-22- and -17A-producing T helper cells in cholangiocarcinoma related to liver fluke infection. Microbiol Immunol 2017; 61:345-354. [PMID: 28718957 DOI: 10.1111/1348-0421.12500] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 06/20/2017] [Accepted: 07/03/2017] [Indexed: 12/19/2022]
Abstract
Cholangiocarcinoma (CCA) associated with liver fluke infection involves inflammatory and immune processes; however, whether these involve the proinflammatory cytokine IL-17A and proliferative cytokine IL-22 remains unclear. Here, numbers of IL-22- and IL-17A-producing Th cells and cytokine concentrations in 30 patients with CCA and long-term liver fluke infection, 40 patients with liver-fluke infection but not CCA, and 16 healthy controls were compared. Analyses were performed using immunohistochemistry, flow cytometry, ELISA and RT-PCR. Immunohistochemical staining showed weaker expression of IL-22 and IL-17A in patients with CCA with than in those without liver fluke infection (P < 0.01). Flow cytometry revealed significantly greater median proportions of IL-22-producing T helper cells in patients with CCA (2.2%) than in those without it (0.69%) or controls (0.4%, P < 0.001). Similar results were obtained for IL-17A-producing T helper cells. ELISA revealed plasma concentrations of IL-22 were 1.3-fold higher in patients with CCA than in those without it and 4.6-fold higher than in controls (P < 0.001). Plasma concentrations of IL-17A were 2.5-fold higher in patients with CCA than in those without it, and 21-fold higher than in controls (P < 0.001). Amounts of IL-22 and IL-17A mRNAs in blood were significantly higher in patients with CCA than in the other two groups. Proportions of CD4+ CD45RO+ T cells producing IL-22 correlated with proportions producing IL-17A (r = 0.759; P < 0.001), and plasma concentrations of IL-22 correlated with those of IL-17A (r = 0.726; P < 0.001). These results suggest that both IL-17A and IL-22 affect development of CCA related to liver fluke infection.
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Affiliation(s)
- Si-Biao Su
- Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Jian-Feng Zhang
- Department of Emergency Medicine, Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Fei-Fei Huang
- Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Yu Cen
- Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Hai-Xing Jiang
- Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
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Chichelnitskiy E, Himmelseher B, Bachmann M, Pfeilschifter J, Mühl H. Hypothermia Promotes Interleukin-22 Expression and Fine-Tunes Its Biological Activity. Front Immunol 2017; 8:742. [PMID: 28706520 PMCID: PMC5489602 DOI: 10.3389/fimmu.2017.00742] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 06/12/2017] [Indexed: 01/15/2023] Open
Abstract
Disturbed homeostasis as a result of tissue stress can provoke leukocyte responses enabling recovery. Since mild hypothermia displays specific clinically relevant tissue-protective properties and interleukin (IL)-22 promotes healing at host/environment interfaces, effects of lowered ambient temperature on IL-22 were studied. We demonstrate that a 5-h exposure of endotoxemic mice to 4°C reduces body temperature by 5.0° and enhances splenic and colonic il22 gene expression. In contrast, tumor necrosis factor-α and IL-17A were not increased. In vivo data on IL-22 were corroborated using murine splenocytes and human peripheral blood mononuclear cells (PBMC) cultured upon 33°C and polyclonal T cell activation. Upregulation by mild hypothermia of largely T-cell-derived IL-22 in PBMC required monocytes and associated with enhanced nuclear T-cell nuclear factor of activated T cells (NFAT)-c2. Notably, NFAT antagonism by cyclosporin A or FK506 impaired IL-22 upregulation at normothermia and entirely prevented its enhanced expression upon hypothermic culture conditions. Data suggest that intact NFAT signaling is required for efficient IL-22 induction upon normothermic and hypothermic conditions. Hypothermia furthermore boosted early signal transducer and activator of transcription 3 activation by IL-22 and shaped downstream gene expression in epithelial-like cells. Altogether, data indicate that hypothermia supports and fine-tunes IL-22 production/action, which may contribute to regulatory properties of low ambient temperature.
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Affiliation(s)
- Evgeny Chichelnitskiy
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Frankfurt, Germany
| | - Britta Himmelseher
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Frankfurt, Germany
| | - Malte Bachmann
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Frankfurt, Germany
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Frankfurt, Germany
| | - Heiko Mühl
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, Frankfurt, Germany
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Bachmann M, Meissner C, Pfeilschifter J, Mühl H. Cooperation between the bacterial-derived short-chain fatty acid butyrate and interleukin-22 detected in human Caco2 colon epithelial/carcinoma cells. Biofactors 2017; 43:283-292. [PMID: 27801948 DOI: 10.1002/biof.1341] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 09/28/2016] [Accepted: 10/04/2016] [Indexed: 12/29/2022]
Abstract
By generating biologically active factors luminal microbiota shape the intestinal micro-milieu thereby regulating pathological processes such as inflammation and carcinogenesis. Preclinical data suggest that bacterial-derived butyrate and the signal transducer and activator of transcription (STAT)-3 activating cytokine interleukin (IL)-22 display concordant protective properties at the inflamed colonic epithelium. Herein, biochemical cooperation between the short-chain fatty acid butyrate and IL-22 was investigated by focusing on human Caco2 colon epithelial/carcinoma cells. We report that physiological levels of butyrate enhance IL-22 signaling thereby enforcing expression of the prototypic STAT3-downstrean target genes α1-antichymotrypsin and suppressor of cytokine signaling (SOCS)-3. A dual mode of butyrate action on the IL-22/STAT3 axis was identified. Butyrate acted by upregulating IL-22R1, the decisive chain of the heterodimeric IL-22 receptor, and, independent from that, has the potential to directly amplify STAT3-mediated gene activation as detected by chromatin immunoprecipitation analysis of STAT3 binding to the SOCS3 promoter. Since trichostatin A acted similarly, inhibition of histone deacetylases is likely at the root of these butyrate biological properties. The mutual benefit gained from interactions between the host and commensal intestinal bacteria-derived factors is an expanding field of research beginning to affect clinical practice. Data presented herein propose a supportive and fine-tuning role for butyrate in IL-22 signaling that might be therapeutically exploited by local butyrate administration or by increasing its bacterial production in the context of a fiber-rich diet. © 2016 BioFactors, 43(2):283-292, 2017.
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Affiliation(s)
- Malte Bachmann
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Carlotta Meissner
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany
| | - Heiko Mühl
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany
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Qiao YY, Liu XQ, Xu CQ, Zhang Z, Xu HW. Interleukin-22 ameliorates acute severe pancreatitis-associated lung injury in mice. World J Gastroenterol 2016; 22:5023-32. [PMID: 27275094 PMCID: PMC4886377 DOI: 10.3748/wjg.v22.i21.5023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 04/11/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential protective effect of exogenous recombinant interleukin-22 (rIL-22) on L-arginine-induced acute severe pancreatitis (SAP)-associated lung injury and the possible signaling pathway involved. METHODS Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase (MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin (HE) staining. Expression of B cell lymphoma/leukemia-2 (Bcl-2), Bcl-xL and IL-22RA1 mRNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot. RESULTS Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group (P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-xL mRNAs in the SAP group was decreased markedly, while the IL-22RA1 mRNA expression was increased significantly relative to the normal control group (P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-xL or IL-22RA1 mRNA (P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the rIL-22 group were significantly lower than those in the SAP group (P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, rIL-22 stimulated the expression of Bcl-2, Bcl-xL and IL-22RA1 mRNAs in the lung (P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the rIL-22 group was significantly higher than that in the PBS group (P < 0.05). CONCLUSION Exogenous recombinant IL-22 protects mice against L-arginine-induced SAP-associated lung injury by enhancing the expression of anti-apoptosis genes through the STAT3 signaling pathway.
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He X, Li H, Chen Y, Chen A, Shan K, Chen J, Zhao H, Zhang X, Cai T. The Effects of IL-22 on the Inflammatory Mediator Production, Proliferation, and Barrier Function of HUVECs. Inflammation 2016; 39:1099-107. [PMID: 27059499 DOI: 10.1007/s10753-016-0341-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aim of this study was to investigate the effects of interleukin (IL)-22 on proliferation function and inflammatory mediator production and barrier function of human umbilical vein endothelial cells (HUVECs). The expression of mRNA was detected by RT-PCR. The proliferation ability of cells was evaluated using a cell counting kit assay. Real-time quantitative PCR and Western blot were used to detect the expression of inflammatory mediators. The endothelial barrier permeability was assessed by measuring permeability to FITC-labeled dextran. The distribution of occludin was detected by immunofluorescence. IL-22R1 mRNA expression was noted in HUVECs. IL-22 could enhance the proliferation ability of HUVECs and suppress lipopolysaccharide (LPS)-induced proliferation inhibition in these cells. IL-22 also enhanced the production of CCL2 and CCL20 by HUVECs. Besides, IL-22 could improve barrier function and decrease LPS-induced increased cellular permeability and inhibit the LPS-induced destruction of occludin in HUVECs. IL-22 may play a protective role in the development of vasculitis.
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Affiliation(s)
- Xian He
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Hui Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Ying Chen
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Aijun Chen
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Kui Shan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Jin Chen
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Hengguang Zhao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xiaojiao Zhang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Tao Cai
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
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Lu Z, Liu R, Huang E, Chu Y. MicroRNAs: New regulators of IL-22. Cell Immunol 2016; 304-305:1-8. [PMID: 27221197 DOI: 10.1016/j.cellimm.2016.05.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/11/2016] [Accepted: 05/16/2016] [Indexed: 12/18/2022]
Abstract
Interleukin-22 (IL-22) is a cytokine that belongs to the IL-10 family of interleukins. It can be produced by T helper 22 (Th22) cells, T helper 1 (Th1) cells, T helper 17 (Th17) cells, natural killer 22 (NK22) cells, natural killer T (NKT) cells, innate lymphoid cells (ILCs), and γδ T cells. IL-22 acts via binding to a heterodimeric transmembrane receptor complex that consists of IL-22R1 and IL-10R2 and mainly contributes to the tissue repair and host defense. Transcription factors such as retinoid orphan receptor γt (RORγt) and signal transducer and activator of transcription 3 (STAT3), have been reported to play important roles in regulation of IL-22 expression. Recently, it has been demonstrated in several studies that microRNAs (miRNAs) potently regulate expression of interleukins, including production of IL-22. Here, we review current knowledge about regulators of IL-22 expression with a particular emphasis on the role of miRNAs.
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Affiliation(s)
- Zhou Lu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China
| | - Ronghua Liu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China
| | - Enyu Huang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; Biotherapy Research Center, Fudan University, Shanghai 200032, People's Republic of China.
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Mühl H. STAT3, a Key Parameter of Cytokine-Driven Tissue Protection during Sterile Inflammation - the Case of Experimental Acetaminophen (Paracetamol)-Induced Liver Damage. Front Immunol 2016; 7:163. [PMID: 27199988 PMCID: PMC4852172 DOI: 10.3389/fimmu.2016.00163] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 04/15/2016] [Indexed: 12/12/2022] Open
Abstract
Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol) overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger-associated molecular patterns (DAMPs) from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT)-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL)-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients, standard therapy may fail and APAP intoxication can proceed toward a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions.
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Affiliation(s)
- Heiko Mühl
- Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe-University Frankfurt am Main , Frankfurt am Main , Germany
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Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques. J Virol 2016; 90:4981-4989. [PMID: 26937040 DOI: 10.1128/jvi.00099-16] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 02/25/2016] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED An altered intestinal microbiome during chronic human immunodeficiency virus (HIV) infection is associated with mucosal dysfunction, inflammation, and disease progression. We performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (FMT) as a potential therapeutic in HIV-infected individuals. Antiretroviral-treated, chronically simian immunodeficiency virus (SIV)-infected rhesus macaques received antibiotics followed by FMT. The greatest microbiota shift was observed after antibiotic treatment. The bacterial community composition at 2 weeks post-FMT resembled the pre-FMT community structure, although differences in the abundances of minor bacterial populations remained. Immunologically, we observed significant increases in the number of peripheral Th17 and Th22 cells and reduced CD4(+) T cell activation in gastrointestinal tissues post-FMT. Importantly, the transplant was well tolerated with no negative clinical side effects. Although this pilot study did not control for the differential contributions of antibiotic treatment and FMT to the observed results, the data suggest that FMT may have beneficial effects that should be further evaluated in larger studies. IMPORTANCE Due to the immunodeficiency and chronic inflammation that occurs during HIV infection, determination of the safety of FMT is crucial to prevent deleterious consequences if it is to be used as a treatment in the future. Here we used the macaque model of HIV infection and performed FMT on six chronically SIV-infected rhesus macaques on antiretroviral treatment. In addition to providing a preclinical demonstration of the safety of FMT in primates infected with a lentivirus, this study provided a unique opportunity to examine the relationships between alterations to the microbiome and immunological parameters. In this study, we found increased numbers of Th17 and Th22 cells as well as decreased activation of CD4(+) T cells post-FMT, and these changes correlated most strongly across all sampling time points with lower-abundance taxonomic groups and other taxonomic groups in the colon. Overall, these data provide evidence that changes in the microbiome, particularly in terms of diversity and changes in minor populations, can enhance immunity and do not have adverse consequences.
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