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Yu T, Yang S, Zhang L, Deng D, Zhang X, Luo K, Gao W, Wang B, Zhang S, Xu Q. SIGIRR plays a dual role in zebrafish infected with Edwardsiella piscicida: Boosting digestive system wellness and mitigating inflammation. FISH & SHELLFISH IMMUNOLOGY 2025; 157:110105. [PMID: 39742930 DOI: 10.1016/j.fsi.2024.110105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/21/2024] [Accepted: 12/29/2024] [Indexed: 01/04/2025]
Abstract
Single immunoglobulin interleukin-1 receptor-associated protein (SIGIRR) negatively regulates the inflammatory response induced by bacterial infection by inhibiting the excessive synthesis of inflammatory mediators and overactivation. This inhibitory mechanism reduces the fish's susceptibility to pathogens and enhances survival rates. Zebrafish lacking the SIGIRR gene were generated using CRISPR/Cas9 gene knockout technology. In a zebrafish model infected with Edwardsiella piscicida, researchers found that SIGIRR gene deletion led to a significant increase in the activation of both inflammatory and anti-inflammatory factors. This deletion also resulted in intestinal villus epithelium damage, epithelial shedding, separation of the epithelium and lamina propria, and a severe reduction in goblet cells. After E. piscicida infection, the survival rate of SIGIRR-/- zebrafish was significantly reduced, and the number of E. piscicida in the body was also significantly increased. Intestinal acid phosphatase activity in SIGIRR-/- zebrafish was markedly elevated compared to wild-type (WT) zebrafish. Furthermore, the intestinal mucosal layer and villus thickness in SIGIRR-/- zebrafish were reduced compared to WT zebrafish. The enzymatic activities of lipase and lysozyme in the intestines of SIGIRR-/- zebrafish were significantly lower than in WT zebrafish. This study reveals the detrimental effects of SIGIRR gene deletion on the intestinal health of zebrafish, leading to decreased innate immune capacity and increased susceptibility to bacterial infections.
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Affiliation(s)
- Ting Yu
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Shuo Yang
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Lifeng Zhang
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Dan Deng
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Xiao Zhang
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Kai Luo
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Weihua Gao
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China
| | - Bei Wang
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, 524088, China
| | - Shuhuan Zhang
- Sturgeon Healthy Breeding and Medicinal Value Research Center, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China
| | - Qiaoqing Xu
- Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434024, China.
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Perruzza L, Rezzonico Jost T, Raneri M, Gargari G, Palatella M, De Ponte Conti B, Seehusen F, Heckmann J, Viemann D, Guglielmetti S, Grassi F. Protection from environmental enteric dysfunction and growth improvement in malnourished newborns by amplification of secretory IgA. Cell Rep Med 2024; 5:101639. [PMID: 38959887 PMCID: PMC11293325 DOI: 10.1016/j.xcrm.2024.101639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 04/04/2024] [Accepted: 06/11/2024] [Indexed: 07/05/2024]
Abstract
Environmental enteric dysfunction (EED) is a condition associated with malnutrition that can progress to malabsorption and villous atrophy. Severe EED results in linear growth stunting, slowed neurocognitive development, and unresponsiveness to oral vaccines. Prenatal exposure to malnutrition and breast feeding by malnourished mothers replicates EED. Pups are characterized by deprivation of secretory IgA (SIgA) and altered development of the gut immune system and microbiota. Extracellular ATP (eATP) released by microbiota limits T follicular helper (Tfh) cell activity and SIgA generation in Peyer's patches (PPs). Administration of a live biotherapeutic releasing the ATP-degrading enzyme apyrase to malnourished pups restores SIgA levels and ameliorates stunted growth. SIgA is instrumental in improving the growth and intestinal immune competence of mice while they are continuously fed a malnourished diet. The analysis of microbiota composition suggests that amplification of endogenous SIgA may exert a dominant function in correcting malnourishment dysbiosis and its consequences on host organisms, irrespective of the actual microbial ecology.
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Affiliation(s)
- Lisa Perruzza
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
| | - Tanja Rezzonico Jost
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland
| | - Matteo Raneri
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland
| | - Giorgio Gargari
- Division of Food Microbiology and Bioprocesses, Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, 20133 Milan, Italy
| | - Martina Palatella
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland
| | - Benedetta De Ponte Conti
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland; Graduate School of Cellular and Molecular Sciences, University of Bern, 3012 Bern, Switzerland
| | - Frauke Seehusen
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland
| | - Julia Heckmann
- Department of Pediatrics, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Dorothee Viemann
- Department of Pediatrics, University Hospital Würzburg, 97080 Würzburg, Germany; Cluster of Excellence RESIST (EXC 2355), Hannover Medical School, 30625 Hannover, Germany; Center for Infection Research, University Würzburg, 97080 Würzburg, Germany
| | - Simone Guglielmetti
- Department of Biotechnology and Biosciences (BtBs), University of Milano-Bicocca, 20126 Milan, Italy
| | - Fabio Grassi
- Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
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Yu H, Xu Y, Imani S, Zhao Z, Ullah S, Wang Q. Navigating ESKAPE Pathogens: Considerations and Caveats for Animal Infection Models Development. ACS Infect Dis 2024; 10:2336-2355. [PMID: 38866389 PMCID: PMC11249778 DOI: 10.1021/acsinfecdis.4c00007] [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: 01/04/2024] [Revised: 05/19/2024] [Accepted: 05/29/2024] [Indexed: 06/14/2024]
Abstract
The misuse of antibiotics has led to the global spread of drug-resistant bacteria, especially multi-drug-resistant (MDR) ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). These opportunistic bacteria pose a significant threat, in particular within hospitals, where they cause nosocomial infections, leading to substantial morbidity and mortality. To comprehensively explore ESKAPE pathogenesis, virulence, host immune response, diagnostics, and therapeutics, researchers increasingly rely on necessitate suitable animal infection models. However, no single model can fully replicate all aspects of infectious diseases. Notably when studying opportunistic pathogens in immunocompetent hosts, rapid clearance by the host immune system can limit the expression of characteristic disease symptoms. In this study, we examine the critical role of animal infection models in understanding ESKAPE pathogens, addressing limitations and research gaps. We discuss applications and highlight key considerations for effective models. Thoughtful decisions on disease replication, parameter monitoring, and data collection are crucial for model reliability. By meticulously replicating human diseases and addressing limitations, researchers maximize the potential of animal infection models. This aids in targeted therapeutic development, bridges knowledge gaps, and helps combat MDR ESKAPE pathogens, safeguarding public health.
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Affiliation(s)
- Haojie Yu
- Key
Laboratory of Artificial Organs and Computational Medicine in Zhejiang
Province, Key Laboratory of Pollution Exposure and Health Intervention
of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang China
- Stomatology
Hospital, School of Stomatology, Zhejiang University School of Medicine,
Zhejiang Provincial Clinical Research Center for Oral Diseases, Key
Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China
| | - Yongchang Xu
- Key
Laboratory of Aging and Cancer Biology of Zhejiang Province, School
of Basic Medical Sciences, Hangzhou Normal
University, Hangzhou 311121, China
| | - Saber Imani
- Shulan
International Medical College, Zhejiang
Shuren University, Hangzhou 310015, Zhejiang China
| | - Zhuo Zhao
- Department
of Computer Science and Engineering, University
of Notre Dame, Notre
Dame, Indiana 46556, United States
| | - Saif Ullah
- Department
of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, United States
| | - Qingjing Wang
- Key
Laboratory of Artificial Organs and Computational Medicine in Zhejiang
Province, Key Laboratory of Pollution Exposure and Health Intervention
of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang China
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Gilliland A, Chan JJ, De Wolfe TJ, Yang H, Vallance BA. Pathobionts in Inflammatory Bowel Disease: Origins, Underlying Mechanisms, and Implications for Clinical Care. Gastroenterology 2024; 166:44-58. [PMID: 37734419 DOI: 10.1053/j.gastro.2023.09.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/28/2023] [Accepted: 09/07/2023] [Indexed: 09/23/2023]
Abstract
The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn's disease (CD) and ulcerative colitis (UC). Although evidence suggests dysbiosis and loss of beneficial microbial species can exacerbate IBD, many new studies have identified microbes with pathogenic qualities, termed "pathobionts," within the intestines of patients with IBD. The concept of pathobionts initiating or driving the chronicity of IBD has largely focused on the putative aggravating role that adherent invasive Escherichia coli may play in CD. However, recent studies have identified additional bacterial and fungal pathobionts in patients with CD and UC. This review will highlight the characteristics of these pathobionts and their implications for IBD treatment. Beyond exploring the origins of pathobionts, we discuss those associated with specific clinical features and the potential mechanisms involved, such as creeping fat (Clostridium innocuum) and impaired wound healing (Debaryomyces hansenii) in patients with CD as well as the increased fecal proteolytic activity (Bacteroides vulgatus) seen as a biomarker for UC severity. Finally, we examine the potential impact of pathobionts on current IBD therapies, and several new approaches to target pathobionts currently in the early stages of development. Despite recognizing that pathobionts likely contribute to the pathogenesis of IBD, more work is needed to define their modes of action. Determining whether causal relationships exist between pathobionts and specific disease characteristics could pave the way for improved care for patients, particularly for those not responding to current IBD therapies.
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Affiliation(s)
- Ashley Gilliland
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Jocelyn J Chan
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Travis J De Wolfe
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Hyungjun Yang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Bruce A Vallance
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada.
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Wan T, Wang Y, He K, Zhu S. Microbial sensing in the intestine. Protein Cell 2023; 14:824-860. [PMID: 37191444 PMCID: PMC10636641 DOI: 10.1093/procel/pwad028] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).
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Affiliation(s)
- Tingting Wan
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Yalong Wang
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Kaixin He
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Shu Zhu
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
- Department of Digestive Disease, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
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Chalalai T, Kamiyama N, Saechue B, Sachi N, Ozaka S, Ariki S, Dewayani A, Soga Y, Kagoshima Y, Ekronarongchai S, Okumura R, Kayama H, Takeda K, Kobayashi T. TRAF6 signaling in dendritic cells plays protective role against infectious colitis by limiting C. rodentium infection through the induction of Th1 and Th17 responses. Biochem Biophys Res Commun 2023; 669:103-112. [PMID: 37269592 DOI: 10.1016/j.bbrc.2023.05.059] [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: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/05/2023]
Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a pivotal role in the induction of inflammatory responses not only in innate immune cells but also in non-immune cells, leading to the activation of adaptive immunity. Signal transduction mediated by TRAF6, along with its upstream molecule MyD88 in intestinal epithelial cells (IECs) is crucial for the maintenance of mucosal homeostasis following inflammatory insult. The IEC-specific TRAF6-deficient (TRAF6ΔIEC) and MyD88-deficient (MyD88ΔIEC) mice exhibit increased susceptibility to DSS-induced colitis, emphasizing the critical role of this pathway. Moreover, MyD88 also plays a protective role in Citrobacter rodentium (C. rodentium) infection-induced colitis. However, its pathological role of TRAF6 in infectious colitis remains unclear. To investigate the site-specific roles of TRAF6 in response to enteric bacterial pathogens, we infected TRAF6ΔIEC and dendritic cell (DC)-specific TRAF6-deficient (TRAF6ΔDC) mice with C. rodentium and found that the pathology of infectious colitis was exacerbated with significantly decreased survival rates in TRAF6ΔDC mice, but not in TRAF6ΔIEC mice, compared to those in control mice. TRAF6ΔDC mice showed increased bacterial burdens, marked disruption of epithelial and mucosal structures with increased infiltration of neutrophils and macrophages, and elevated cytokine levels in the colon at the late stages of infection. The frequencies of IFN-γ producing Th1 cells and IL-17A producing Th17 cells in the colonic lamina propria were significantly reduced in TRAF6ΔDC mice. Finally, we demonstrated that TRAF6-deficient DCs failed to produce IL-12 and IL-23 in response to C. rodentium stimulation, and to induce both Th1 and Th17 cells in vitro. Thus, TRAF6 signaling in DCs, but not in IECs, protects against colitis induced by C. rodentium infection by producing IL-12 and IL-23 that induce Th1 and Th17 responses in the gut.
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Affiliation(s)
| | - Naganori Kamiyama
- Department of Infectious Disease Control, Faculty of Medicine, Japan.
| | - Benjawan Saechue
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | - Nozomi Sachi
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | - Sotaro Ozaka
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | - Shimpei Ariki
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | - Astri Dewayani
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | - Yasuhiro Soga
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | - Yomei Kagoshima
- Department of Infectious Disease Control, Faculty of Medicine, Japan
| | | | - Ryu Okumura
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Hisako Kayama
- Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka, Japan
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Takashi Kobayashi
- Department of Infectious Disease Control, Faculty of Medicine, Japan; Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Oita, Japan.
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Reza Lahimchi M, Eslami M, Yousefi B. Interleukin-35 and Interleukin-37 anti-inflammatory effect on inflammatory bowel disease: Application of non-coding RNAs in IBD therapy. Int Immunopharmacol 2023; 117:109932. [PMID: 37012889 DOI: 10.1016/j.intimp.2023.109932] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/05/2023] [Accepted: 02/21/2023] [Indexed: 03/11/2023]
Abstract
Inflammatory bowel disease (IBD) is a widespread autoimmune disease that may even be life-threatening. IBD is divided into two major subtypes: ulcerative colitis and Crohn's disease. Interleukin (IL)-35 and IL-37 are anti-inflammatory cytokines that belong to IL-12 and IL-1 families, respectively. Their recruitment relieves inflammation in various autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and IBD. Regulatory T cells (Tregs) and regulatory B cells (Bregs) are the primary producers of IL-35/IL-37. IL-35 and IL-37 orchestrate the regulation of the immune system through two main strategies: Blocking nuclear transcription factor kappa-B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways or promoting the proliferation of Tregs and Bregs. Moreover, IL-35 and IL-37 can also inhibit inflammation by adjusting the T helper (Th)17/Treg ratio balance. Among the anti-inflammatory cytokines, IL-35 and IL-37 have significant potential to reduce intestinal inflammation. Therefore, administering IL-35/IL-37-based drugs or blocking their inhibitor microRNAs could be a promising approach to alleviate IBD symptoms. Overall, in this review article, we summarized the therapeutic application of IL-35 and IL-37 in both human and experimental models of IBD. Also, it is hoped that this practical information will reach beyond IBD therapy and shed some light on treating all intestinal inflammations.
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Tian F, Lei J, Ni Y, Zhong D, Xie N, Ma J, Wang H, Si S, Wu Y, Jiang T. Regulation of CD18 stability by SIGIRR-modulated ubiquitination: new insights into the relationship between innate immune response and acute lung injury. FEBS J 2022; 290:2721-2743. [PMID: 36527283 DOI: 10.1111/febs.16708] [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: 01/28/2022] [Revised: 10/27/2022] [Accepted: 11/03/2022] [Indexed: 12/23/2022]
Abstract
Inappropriate accumulation of alveolar macrophages (AMs) and subsequent excessive production of immune responses play critical roles in the pathogenesis of acute lung injury (ALI), but the core negative regulators governing innate signalling in AMs are ill defined. We have previously shown that single immunoglobin IL-1 receptor-related protein (SIGIRR), a negative regulator of IL-1 receptor and Toll-like receptor signalling, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in AMs. To address the biological relevance of SIGIRR in vivo, we generated a murine ALI model via intratracheal instillation of LPS. Intriguingly, SIGIRR expression was observed to be decreased in resident and recruited macrophages during ALI. This decrease was associated with parallel induction in CD18 protein levels in LPS-challenged lung tissues. Through intranasal injection of SIGIRR lentiviral particles studies, we showed that the overexpression of SIGIRR attenuated recruitment of macrophages and neutrophils, decreased production of inflammatory cytokines and ameliorated pathological changes in lungs. Whilst exploring the basis for this phenotype, SIGIRR was found to be coexpressed with CD18 in AMs, and SIGIRR potentiated the instability of CD18 protein via enhancement of its ubiquitination and proteasome degradation. Conversely, by using CD18-/- mice, we further observed that CD18 deletion completely abolished the therapeutic effects of overexpression of SIGIRR on LPS-induced ALI. Mover, overexpression of CD18 in AMs promoted adhesion to ECM components, enhanced TLR4-mediated inflammasome activation and thereby potentiated IL-1β production. These data collectively identify SIGIRR/CD18 as a key negative regulatory circuit maintaining innate immune homeostasis in AMs along the pathogenesis of ALI.
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Affiliation(s)
- Feng Tian
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jie Lei
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Yunfeng Ni
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Daixing Zhong
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Nianlin Xie
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jun Ma
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Haiqiang Wang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Shaokui Si
- Department of Respiration, Third Hospital of Baoji, Baoji, China
| | - Yumei Wu
- Department of Pharmacy, Air Force Medical University, Xi'an, China
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
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Ren C, Liu F, Xing C, Zhao R, Tang X, Liu M, Gao W, Shen J. IL-37 alleviates liver granuloma caused by Schistosoma japonicum infection by inducing alternative macrophage activation. Parasit Vectors 2022; 15:300. [PMID: 36002836 PMCID: PMC9404629 DOI: 10.1186/s13071-022-05420-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/26/2022] [Indexed: 11/10/2022] Open
Abstract
Background Hepatic macrophages regulate liver granuloma formation and fibrosis caused by infection with Schistosoma japonicum, with the manner of regulation dependent on macrophage activation state. Interleukin (IL)-37 may have immunomodulatory effects on macrophages. However, whether IL-37 can affect liver granuloma formation and fibrosis by affecting the polarization of macrophages in S. japonicum infection remains unclear. The aim of this study was to investigate IL-37-affected macrophage polarization in liver granuloma formation and fibrosis in S. japonicum infection. Methods An enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of IL-37 in the serum of patients with acute S. japonicum infection and in the serum of healthy people. Recombinant IL-37 (rIL-37), CPP-IgG2Fc-IL-37 and no CPP-IgG2Fc-IL-37 proteins were injected into S. japonicum-infected mice every 3 days for a total of 6 times from day 24 post infection onwards. Subsequently, ELISA, quantitative reverse transcription-PCR, fluorescence-activated cell sorting and western blot were used to analyze whether IL-37 inhibits the formation of liver granulomas and the development of liver fibrosis by regulating the phenotypic transition of macrophages. Finally, the three IL-37 proteins and SIS3, a Smad3 inhibitor, were co-cultured in mouse peritoneal macrophages to explore the mechanism underlying the promotion of the polarization of M0 macrophages to the M2 phenotype by IL-37. Results Serum IL-37 levels were upregulated in schistosomiasis patients, and this increased level of IL-37 protein apparently alleviated the liver granuloma of mice in infection models. It also could induce liver and peritoneal macrophages to polarize to the M2 phenotype in S. japonicum-infected mice. The S. japonicum-infected mice injected with CPP-IgG2Fc-IL-37 group exhibited the most obvious improvement in inflammatory reaction against the liver granuloma. The number and ratio of M2 macrophages in the liver and peritoneal cavity were significantly higher in the three IL-37 protein groups, especially in the CPP-IgG2Fc-IL-37 group, compared to the controls. Similar results were also found regarding liver function damage. IL-37 induced macrophage M2 polarization by promoting AMP-activated protein kinase (AMPK) phosphorylation in vitro. Among all groups, the activation of AMPK was most significant in the CPP-IgG2Fc-IL-37 group, and it was found that SMAD3 could enhance the anti-inflammatory function of IL-37. Conclusions The results show that IL-37 was able to promote the polarization of macrophages to the M2 phenotype, thereby inhibiting the development of schistosomiasis. In comparison to the rIL-37 protein, the CPP-IgG2Fc-IL-37 protein has the advantages of being effective in small doses and having fewer side effects and a better efficacy. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-022-05420-6.
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Affiliation(s)
- Cuiping Ren
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Fengchun Liu
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Anhui Provincial Center for Clinical Laboratories, The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230032, China
| | - Chen Xing
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Ruyu Zhao
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Xiaoxue Tang
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Miao Liu
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Wenda Gao
- Antagen Institute for Biomedical Research, Boston, MA, 02118, USA.
| | - Jijia Shen
- Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology; Anhui Provincial Laboratory of Zoonoses; Laboratory of Tropical and Parasitic Diseases Control; School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
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10
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IL-1R8 as Pathoimmunological Marker for Severity of Canine Chronic Enteropathy. Vet Sci 2022; 9:vetsci9060295. [PMID: 35737347 PMCID: PMC9229266 DOI: 10.3390/vetsci9060295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 12/02/2022] Open
Abstract
Chronic enteropathy (CE) is a severe multifactorial gastrointestinal disease that affects dogs and is driven by poorly characterized inflammatory pathways. Imbalance of pro-inflammatory response regulators, including IL-1R8, may be due to different factors, among which the infection with Helicobacteraceae is known to lead to a vicious circle in which excessive pro-inflammatory signaling and gastrointestinal injury reinforce each other and boost the disease. We investigated the expression of IL-1R8 in large intestine biopsies of dogs with or without clinical signs of CE and with previously assessed enterohepatic Helicobacter spp. colonization status by mean of quantitative real-time PCR. Our study revealed that IL-1R8 is downregulated in both acutely (p = 0.0074) and chronically (p = 0.0159) CE affected dogs compared to healthy controls. The data also showed that IL-1R8 expression tends to decrease with colonization by Helicobacter spp. Interestingly, a negative correlation was detected between the level of expression of IL-1R8 and the severity of macroscopic lesions identified by endoscopy and the crypt hyperplasia score. We further compared the expression levels between males and females and found no statistically significant difference between the two groups. No significant difference was observed in IL-1R8 expression profiles with the age of the animals either. Interestingly, an association was uncovered between IL-1R8 expression level and dog breed. Together, our data advance knowledge on gastrointestinal pathoimmunology in dogs and highlight the potential utilization of IL-1R8 as a diagnostic, prognostic and therapeutic biomarker for canine chronic enteropathy.
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11
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Abraham C, Abreu MT, Turner JR. Pattern Recognition Receptor Signaling and Cytokine Networks in Microbial Defenses and Regulation of Intestinal Barriers: Implications for Inflammatory Bowel Disease. Gastroenterology 2022; 162:1602-1616.e6. [PMID: 35149024 PMCID: PMC9112237 DOI: 10.1053/j.gastro.2021.12.288] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/30/2021] [Accepted: 12/10/2021] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel disease is characterized by defects in epithelial function and dysregulated inflammatory signaling by lamina propria mononuclear cells including macrophages and dendritic cells in response to microbiota. In this review, we focus on the role of pattern recognition receptors in the inflammatory response as well as epithelial barrier regulation. We explore cytokine networks that increase inflammation, regulate paracellular permeability, cause epithelial damage, up-regulate epithelial proliferation, and trigger restitutive processes. We focus on studies using patient samples as well as speculate on pathways that can be targeted to more holistically treat patients with inflammatory bowel disease.
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Affiliation(s)
- Clara Abraham
- Department of Internal Medicine, Yale University, New Haven, Connecticut.
| | - Maria T. Abreu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Miami Leonard Miller School of Medicine, Miami, FL
| | - Jerrold R. Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
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12
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Supino D, Minute L, Mariancini A, Riva F, Magrini E, Garlanda C. Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease. Front Immunol 2022; 13:804641. [PMID: 35211118 PMCID: PMC8861086 DOI: 10.3389/fimmu.2022.804641] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.
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Affiliation(s)
- Domenico Supino
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Luna Minute
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Italy
| | - Andrea Mariancini
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Italy
| | - Federica Riva
- Department of Veterinary Medicine, University of Milan, Milan, Italy
| | - Elena Magrini
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Cecilia Garlanda
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, Italy
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13
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Donda KT, Torres BA, Khashu M, Maheshwari A. Single Nucleotide Polymorphisms in Neonatal Necrotizing Enterocolitis. Curr Pediatr Rev 2022; 18:197-209. [PMID: 35040407 DOI: 10.2174/1573396318666220117091621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/10/2021] [Accepted: 11/16/2021] [Indexed: 11/22/2022]
Abstract
The etiopathogenesis of necrotizing enterocolitis (NEC) remains unclear, but increasing information suggests that the risk and severity of NEC may be influenced by single nucleotide polymorphisms in many genes. In this article, we have reviewed gene variations that have either been specifically identified in NEC or have been noted in other inflammatory bowel disorders with similar histopathological abnormalities. We present evidence from our own peer-reviewed laboratory studies and data from an extensive literature search in the databases PubMed, EMBASE, and Scopus. To avoid bias in the identification of existing studies, search keywords were short-listed both from our own studies and from PubMed's Medical Subject Heading (MeSH) thesaurus.
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Affiliation(s)
- Keyur T Donda
- Department of Pediatrics, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA
| | - Benjamin A Torres
- Department of Pediatrics, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA
| | - Minesh Khashu
- Poole Hospital NHS Foundation Trust and Bournemouth University, Poole, United Kingdom
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins University, Baltimore, ML, USA
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14
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Probiotics and Trained Immunity. Biomolecules 2021; 11:biom11101402. [PMID: 34680035 PMCID: PMC8533468 DOI: 10.3390/biom11101402] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/09/2021] [Accepted: 09/15/2021] [Indexed: 12/17/2022] Open
Abstract
The characteristics of innate immunity have recently been investigated in depth in several research articles, and original findings suggest that innate immunity also has a memory capacity, which has been named “trained immunity”. This notion has revolutionized our knowledge of the innate immune response. Thus, stimulation of trained immunity represents a therapeutic alternative that is worth exploring. In this context, probiotics, live microorganisms which when administered in adequate amounts confer a health benefit on the host, represent attractive candidates for the stimulation of trained immunity; however, although numerous studies have documented the beneficial proprieties of these microorganisms, their mechanisms of action are not yet fully understood. In this review, we propose to explore the putative connection between probiotics and stimulation of trained immunity.
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15
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SIGIRR Mutation in Human Necrotizing Enterocolitis (NEC) Disrupts STAT3-Dependent microRNA Expression in Neonatal Gut. Cell Mol Gastroenterol Hepatol 2021; 13:425-440. [PMID: 34563711 PMCID: PMC8688179 DOI: 10.1016/j.jcmgh.2021.09.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Single immunoglobulin interleukin-1-related receptor (SIGIRR) is a major inhibitor of Toll-like receptor signaling. Our laboratory identified a novel SIGIRR stop mutation (p.Y168X) in an infant who died of severe necrotizing enterocolitis (NEC). Herein, we investigated the mechanisms by which SIGIRR mutations induce Toll-like receptor hyper-responsiveness in the neonatal gut, disrupting postnatal intestinal adaptation. METHODS Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was used to generate transgenic mice encoding the SIGIRR p.Y168X mutation. Ileal lysates, mouse intestinal epithelial cell (IEC) lysates, and intestinal sections were used to assess inflammation, signal transducer and activator of transcription 3 (STAT3) phosphorylation, microRNA (miRNA), and interleukin-1-related-associated kinase 1 (IRAK1) expression. Western blot, quantitative reverse-transcription polymerase chain reaction(qRT-PCR), and luciferase assays were performed to investigate SIGIRR-STAT3 signaling in human intestinal epithelial cells (HIEC) expressing wild-type or SIGIRR (p.Y168X) plasmids. RESULTS SigirrTg mice showed increased intestinal inflammation and nuclear factor-κB activation concomitant with decreased IEC expression of miR-146a and miR-155. Mechanistic studies in HIECs showed that although SIGIRR induced STAT3-mediated expression of miR-146a and miR-155, the p.Y168X mutation disrupted SIGIRR-mediated STAT3-dependent miRNA expression. Chromatin immunoprecipitation and luciferase assays showed that SIGIRR activation of STAT3-induced miRNA expression is dependent on IRAK1. Both in HIECs and in the mouse intestine, decreased expression of miR-146a observed with the p.Y168X mutation increased expression of IRAK1, a protein whose down-regulation is important for postnatal gut adaptation. CONCLUSIONS Our results uncover a novel pathway (SIGIRR-STAT3-miRNA-IRAK1 repression) by which SIGIRR regulates postnatal intestine adaptation, which is disrupted by a SIGIRR mutation identified in human NEC. These data provide new insights into how human genetic mutations in SIGIRR identified in NEC result in loss of postnatal intestinal immune tolerance.
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16
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Gupta T, Kaur H, Kapila S, Kapila R. Lactobacillus fermentum (MTCC-5898) alleviates Escherichia coli-induced inflammatory responses in intestinal epithelial cells by modulating immune genes and NF-κB signalling. J Appl Microbiol 2021; 131:3008-3017. [PMID: 33999475 DOI: 10.1111/jam.15153] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 02/06/2023]
Abstract
AIM Dietary intervention using probiotic bacteria has emerged as a promising preventive strategy in addressing foodborne infections or gastrointestinal disorders. This study investigated the immunomodulatory effects of Lactobacillus fermentum (MTCC-5898) on Escherichia coli-induced inflammatory responses in intestinal epithelial cells. METHODS AND RESULTS The immune response of intestinal cells (Caco-2) in the presence of probiotic Lact. fermentum was determined during exclusion, competition and displacement of E. coli as the inflammatory agent. To achieve this objective, transcriptional modulation of key immune-related genes (cytokines, pattern recognition receptors and NF-κB), release of cytokines and nuclear translocation of the NF-κB subunit p-65 were studied. Expression of pro-inflammatory cytokines IL-8, TNF-α, IFN-ϒ and IL-23 was high in E. coli-exposed intestinal cells. However, overexpression of these E. coli-induced pro-inflammatory cytokines was prevented by Lact. fermentum during exclusion and competition assays. It also modulated the transcriptional expression of regulatory cytokines (IL-10 and TGF-β), pattern recognition receptors (TLR-2 and TLR-4) and genes associated with master inflammatory regulators (NF-κB and SIGIRR) to reduce E. coli-induced inflammation. The protective effect of Lact. fermentum was further confirmed by suppression of nuclear translocation of cytoplasmic NF-κB subunit (p-65). CONCLUSION Lactobacillus fermentum alleviated E. coli-induced inflammatory responses by modulating the NF-κB signalling besides pro-inflammatory and regulatory cytokines expression. SIGNIFICANCE AND IMPACT OF THE STUDY Lactobacillus fermentum holds significant promise as a potent nutraceutical that prevents and manages inflammatory gut-associated dysfunctions.
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Affiliation(s)
- T Gupta
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
| | - H Kaur
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
| | - S Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
| | - R Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
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17
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Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids. Sci Rep 2021; 11:8206. [PMID: 33859245 PMCID: PMC8050237 DOI: 10.1038/s41598-021-87592-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/25/2021] [Indexed: 12/13/2022] Open
Abstract
Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by suppressing inflammatory signaling.
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18
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Mousavi S, Bereswill S, Heimesaat MM. Murine Models for the Investigation of Colonization Resistance and Innate Immune Responses in Campylobacter Jejuni Infections. Curr Top Microbiol Immunol 2021; 431:233-263. [PMID: 33620654 DOI: 10.1007/978-3-030-65481-8_9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Human infections with the food-borne pathogen Campylobacter jejuni are progressively increasing worldwide and constitute a significant socioeconomic burden to mankind. Intestinal campylobacteriosis in humans is characterized by bloody diarrhea, fever, abdominal pain, and severe malaise. Some individuals develop chronic post-infectious sequelae including neurological and autoimmune diseases such as reactive arthritis and Guillain-Barré syndrome. Studies unraveling the molecular mechanisms underlying campylobacteriosis and post-infectious sequelae have been hampered by the scarcity of appropriate experimental in vivo models. Particularly, conventional laboratory mice are protected from C. jejuni infection due to the physiological colonization resistance exerted by the murine gut microbiota composition. Additionally, as compared to humans, mice are up to 10,000 times more resistant to C. jejuni lipooligosaccharide (LOS) constituting a major pathogenicity factor responsible for the immunopathological host responses during campylobacteriosis. In this chapter, we summarize the recent progress that has been made in overcoming these fundamental obstacles in Campylobacter research in mice. Modification of the murine host-specific gut microbiota composition and sensitization of the mice to C. jejuni LOS by deletion of genes encoding interleukin-10 or a single IL-1 receptor-related molecule as well as by dietary zinc depletion have yielded reliable murine infection models resembling key features of human campylobacteriosis. These substantial improvements pave the way for a better understanding of the molecular mechanisms underlying pathogen-host interactions. The ongoing validation and standardization of these novel murine infection models will provide the basis for the development of innovative treatment and prevention strategies to combat human campylobacteriosis and collateral damages of C. jejuni infections.
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Affiliation(s)
- Soraya Mousavi
- Institute of Microbiology, Infectious Diseases and Immunology, Gastrointestinal Microbiology Research Group, Charité-University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt-University of Berlin, Berlin Institute of Health, Berlin, Germany
| | - Stefan Bereswill
- Institute of Microbiology, Infectious Diseases and Immunology, Gastrointestinal Microbiology Research Group, Charité-University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt-University of Berlin, Berlin Institute of Health, Berlin, Germany
| | - Markus M Heimesaat
- Institute of Microbiology, Infectious Diseases and Immunology, Gastrointestinal Microbiology Research Group, Charité-University Medicine Berlin, Corporate Member of Free University Berlin, Humboldt-University of Berlin, Berlin Institute of Health, Berlin, Germany.
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19
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Ledwaba SE, Costa DVS, Bolick DT, Giallourou N, Medeiros PHQS, Swann JR, Traore AN, Potgieter N, Nataro JP, Guerrant RL. Enteropathogenic Escherichia coli Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations, and Increased Intestinal Permeability in a Murine Model. Front Cell Infect Microbiol 2020; 10:595266. [PMID: 33392105 PMCID: PMC7773950 DOI: 10.3389/fcimb.2020.595266] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022] Open
Abstract
Enteropathogenic E. coli (EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC or escN mutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues. Metabolomic changes were also observed in EPEC infected mice with changes in tricarboxylic acid (TCA) cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. The escN mutant colonized the mice with no weight loss or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.
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Affiliation(s)
- Solanka E. Ledwaba
- Department of Microbiology, University of Venda, Thohoyandou, South Africa
| | - Deiziane V. S. Costa
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - David T. Bolick
- Center for Global Health, Division of Infectious Disease and International Health, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Natasa Giallourou
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College, London, England
| | | | - Jonathan R. Swann
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College, London, England
| | - Afsatou N. Traore
- Department of Microbiology, University of Venda, Thohoyandou, South Africa
| | - Natasha Potgieter
- Department of Microbiology, University of Venda, Thohoyandou, South Africa
| | - James P. Nataro
- Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Richard L. Guerrant
- Center for Global Health, Division of Infectious Disease and International Health, University of Virginia School of Medicine, Charlottesville, VA, United States
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20
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Effect of α-Hemolysin Producing E. coli in Two Different Mouse Strains in a DSS Model of Inflammatory Bowel Disease. Microorganisms 2020; 8:microorganisms8121971. [PMID: 33322398 PMCID: PMC7764192 DOI: 10.3390/microorganisms8121971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 12/09/2020] [Indexed: 12/28/2022] Open
Abstract
Background: Phylogroup B2 Escherichia coli have been associated with ulcerative colitis (UC). In this study, we aimed to compare colonization with the UC-associated E. coli p19A in different mice strains, to investigate the role of alpha hemolysin in a UC mouse model. Methods: In this study, Sigirr −/− and C57BL/6 mice were chosen, and UC was induced by adding dextran sulfate sodium (DSS) to the drinking water. The mice were pre-treated with ciprofloxacin. p19A expressing luminescence and GFP, alpha-hemolysin knock out p19A-ΔhlyI II, and non-pathogenic lab E. coli DH10B were cultured in LB broth, and orally gavaged into the mice. Colonization with p19A WT was visualized using an in vivo imaging system. Results: p19A WT colonized the colon, ileum, Peyer’s patches, liver, and spleen of infected C57BL/6 and Sigirr −/− mice. A total of 99% of the p19A WT infected C57BL/6 mice and 29% of the p19A WT infected Sigirr −/− mice survived to the 4th post infection day. Conclusion: UC-associated E. coli p19A WT colonized the intestines of DSS-treated mice and caused extra-intestinal infection. Hemolysin is an important factor in this pathogenesis, since isogenic hemolysin mutants did not cause the same inflammation.
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21
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Suganya K, Liu QF, Koo BS. Santalum album extract exhibits neuroprotective effect against the TLR3-mediated neuroinflammatory response in human SH-SY5Y neuroblastoma cells. Phytother Res 2020; 35:1991-2004. [PMID: 33166007 DOI: 10.1002/ptr.6942] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 09/25/2020] [Accepted: 10/17/2020] [Indexed: 11/10/2022]
Abstract
Neuroinflammation is an inflammatory response in the nervous system that is associated with various neurological diseases including Alzheimer's diseases and others. Many studies evaluated the anti-inflammatory potential of Santalum album (S. album) extract, but none of them analyzed its effects against neuroinflammatory response in vitro. In addition, the precise mechanism underlying the anti-inflammatory effect of the extract has not yet been elucidated. Therefore, in this study, we investigated the effect of S. album extract on modulation of toll-like receptor 3 (TLR3) agonist polyinosnic-polycytidylic acid (PolyI:C)-induced neuroinflammatory response in human neuroblastoma cells. The TLR3-mediated immune response was differentially modulated by S. album extract in SH-SY5Y cells. In addition, treatment of cells with the conditioned medium (CM) of S. album extract significantly increased the mRNA levels of IFN-β, IFN-α, MxA and OAS-1 and decreased IL-6, CXCL8, CCL2 and IP-10. S. album extract has indirectly affected the expression of IFNs and inflammatory cytokines in SH-SY5Y cells. Furthermore, the extract was able to modulate PolyI:C-induced inflammatory response in Caco2 cells. Overall, S. album was capable to attenuate PolyI:C-induced neuroinflammatory effect through the induction of TLR2, TLR4 and the modulation of TLR negative regulators of the TRAF3, IRF3 and NF-κB pathways.
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Affiliation(s)
- Kanmani Suganya
- Department of Oriental Medicine, Dongguk University, Gyeogju, Republic of Korea.,Department of Oriental Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeonggi-do, Republic of Korea
| | - Quan Feng Liu
- Department of Oriental Medicine, Dongguk University, Gyeogju, Republic of Korea.,Department of Oriental Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeonggi-do, Republic of Korea
| | - Byung-Soo Koo
- Department of Oriental Medicine, Dongguk University, Gyeogju, Republic of Korea.,Department of Oriental Neuropsychiatry, Graduate School of Oriental Medicine, Dongguk University, Gyeonggi-do, Republic of Korea
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22
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Yang H, Mirsepasi-Lauridsen HC, Struve C, Allaire JM, Sivignon A, Vogl W, Bosman ES, Ma C, Fotovati A, Reid GS, Li X, Petersen AM, Gouin SG, Barnich N, Jacobson K, Yu HB, Krogfelt KA, Vallance BA. Ulcerative Colitis-associated E. coli pathobionts potentiate colitis in susceptible hosts. Gut Microbes 2020; 12:1847976. [PMID: 33258388 PMCID: PMC7781664 DOI: 10.1080/19490976.2020.1847976] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory condition linked to intestinal microbial dysbiosis, including the expansion of E. coli strains related to extra-intestinal pathogenic E. coli. These "pathobionts" exhibit pathogenic properties, but their potential to promote UC is unclear due to the lack of relevant animal models. Here, we established a mouse model using a representative UC pathobiont strain (p19A), and mice lacking single immunoglobulin and toll-interleukin 1 receptor domain (SIGIRR), a deficiency increasing susceptibility to gut infections. Strain p19A was found to adhere to the cecal mucosa of Sigirr -/- mice, causing modest inflammation. Moreover, it dramatically worsened dextran sodium sulfate-induced colitis. This potentiation was attenuated using a p19A strain lacking α-hemolysin genes, or when we targeted pathobiont adherence using a p19A strain lacking the adhesin FimH, or following treatment with FimH antagonists. Thus, UC pathobionts adhere to the intestinal mucosa, and worsen the course of colitis in susceptible hosts.
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Affiliation(s)
- Hyungjun Yang
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada,CONTACT Hong Bing Yu Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada; Karen
| | - Hengameh Chloé Mirsepasi-Lauridsen
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, Copenhagen, Denmark,Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Struve
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, Copenhagen, Denmark
| | - Joannie M. Allaire
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Adeline Sivignon
- Université Clermont Auvergne, Laboratoire Microbes Intestin Inflammation Et Susceptibilité De l’Hôte (M2ish), Inserm U1071, M2iSH, F-63000, Clermont-Ferrand, France,INRA, Unité Sous Contrat 2018, Clermont-Ferrand, France
| | - Wayne Vogl
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Else S. Bosman
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Caixia Ma
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Abbas Fotovati
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Gregor S. Reid
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Xiaoxia Li
- Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | - Andreas Munk Petersen
- Department of Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark,Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Sébastien G. Gouin
- Université De Nantes, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS 6230, UFR Des Sciences Et Des Techniques, Nantes, France
| | - Nicolas Barnich
- Université Clermont Auvergne, Laboratoire Microbes Intestin Inflammation Et Susceptibilité De l’Hôte (M2ish), Inserm U1071, M2iSH, F-63000, Clermont-Ferrand, France,INRA, Unité Sous Contrat 2018, Clermont-Ferrand, France
| | - Kevan Jacobson
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Hong Bing Yu
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada,CONTACT Hong Bing Yu Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada; Karen
| | - Karen Angeliki Krogfelt
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, Copenhagen, Denmark,Angeliki Krogfelt
| | - Bruce A. Vallance
- Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada,Lead Contact,Bruce A. Vallance
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23
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York TP, Latendresse SJ, Jackson-Cook C, Lapato DM, Moyer S, Wolen AR, Roberson-Nay R, Do EK, Murphy SK, Hoyo C, Fuemmeler BF, Strauss JF. Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth. Epigenetics 2020; 15:1243-1258. [PMID: 32448018 PMCID: PMC7595591 DOI: 10.1080/15592294.2020.1767277] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 03/17/2020] [Accepted: 03/27/2020] [Indexed: 01/07/2023] Open
Abstract
DNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.
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Affiliation(s)
- Timothy P. York
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Colleen Jackson-Cook
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA
- Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA
| | - Dana M. Lapato
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Sara Moyer
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Aaron R. Wolen
- Transplant Research Institute, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Roxann Roberson-Nay
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
| | - Elizabeth K. Do
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA, USA
| | - Susan K. Murphy
- Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina, USA
| | - Catherine Hoyo
- Epidemiology and Environmental Epigenomics Laboratory, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA
| | - Bernard F. Fuemmeler
- Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA, USA
| | - Jerome F. Strauss
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA
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24
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Burgueño JF, Abreu MT. Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol 2020; 17:263-278. [PMID: 32103203 DOI: 10.1038/s41575-019-0261-4] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/20/2019] [Indexed: 02/07/2023]
Abstract
The human gastrointestinal tract is colonized by trillions of microorganisms that interact with the host to maintain structural and functional homeostasis. Acting as the interface between the site of the highest microbial burden in the human body and the richest immune compartment, a single layer of intestinal epithelial cells specializes in nutrient absorption, stratifies microorganisms to limit colonization of tissues and shapes the responses of the subepithelial immune cells. In this Review, we focus on the expression, regulation and functions of Toll-like receptors (TLRs) in the different intestinal epithelial lineages to analyse how epithelial recognition of bacteria participates in establishing homeostasis in the gut. In particular, we elaborate on the involvement of epithelial TLR signalling in controlling crypt dynamics, enhancing epithelial barrier integrity and promoting immune tolerance towards the gut microbiota. Furthermore, we comment on the regulatory mechanisms that fine-tune TLR-driven immune responses towards pathogens and revisit the role of TLRs in epithelial repair after injury. Finally, we discuss how dysregulation of epithelial TLRs can lead to the generation of dysbiosis, thereby increasing susceptibility to colitis and tumorigenesis.
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Affiliation(s)
- Juan F Burgueño
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maria T Abreu
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
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25
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Kanmani P, Kim H. Beneficial effect of immunobiotic strains on attenuation of Salmonella induced inflammatory response in human intestinal epithelial cells. PLoS One 2020; 15:e0229647. [PMID: 32150574 PMCID: PMC7062243 DOI: 10.1371/journal.pone.0229647] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 02/11/2020] [Indexed: 01/14/2023] Open
Abstract
Probiotic bacteria have the ability to modulate host immune responses and have potent therapeutic functional effects against several diseases, including inflammatory diseases. However, beneficial effects of probiotics are strain specific and their interactions with host immune cells to modulate inflammatory response are largely unknown. Intestinal epithelial cells (IECs), which are the first line of defense against invading pathogens, and connects between commensals/probiotics and immune system; therefore, in this study, we used human IECs to assess the probiotic effects of three selected Lactobacillus strains in vitro. An HT-29 colonic epithelial cell and HT-29/blood mononuclear cells co-culture system were stimulated with Lactobacillus followed by Salmonella for different hours, after which the mRNA level of cytokines, β-defensin-2 and negative regulators for TLR signaling and protein levels of ZO-1 and IκB-α were analyzed by real-time polymerase chain reaction and western blot analysis. L. brevis decreased Salmonella induced IL-6, IL-8, MCP-1 and IL-1β levels, whereas L. pentosus suppressed IL-6 and MCP-1 in HT-29 cells. Moreover, L. brevis was able to increase the mRNA levels of A20, Tollip, SIGIRR and IRAKM, while L. pentosus reduced the levels of A20, and IRAKM in response to Salmonella. In addition, decrease in protein level of TNF-α and increase in mRNA level of IL-10 was observed in L. brevis and L. pentosus treated HT-29 cells. Lactobacillus strains were differentially modulated ZO-1 and p-IκB-α in HT-29 cells treated with Salmonella. Overall, the results of this study indicate that Lactobacillus strains attenuate Salmonella induced inflammatory responses through beneficial modulation of TLR negative regulators and the NF-κB pathway.
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Affiliation(s)
- Paulraj Kanmani
- Department of Korean Medicine, Dongguk University, Goyang, Republic of Korea
| | - Hojun Kim
- Department of Korean Medicine, Dongguk University, Goyang, Republic of Korea
- * E-mail:
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26
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Mackos AR, Allen JM, Kim E, Ladaika CA, Gharaibeh RZ, Moore C, Parry NMA, Boyaka PN, Bailey MT. Mice Deficient in Epithelial or Myeloid Cell Iκκβ Have Distinct Colonic Microbiomes and Increased Resistance to Citrobacter rodentium Infection. Front Immunol 2019; 10:2062. [PMID: 31552024 PMCID: PMC6746829 DOI: 10.3389/fimmu.2019.02062] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 08/15/2019] [Indexed: 12/31/2022] Open
Abstract
The colonic microenvironment, stemming from microbial, immunologic, stromal, and epithelial factors, serves as an important determinant of the host response to enteric pathogenic colonization. Infection with the enteric bacterial pathogen Citrobacter rodentium elicits a strong mucosal Th1-mediated colitis and monocyte-driven inflammation activated via the classical NF-κB pathway. Research has focused on leukocyte-mediated signaling as the main driver for C. rodentium-induced colitis, however we hypothesize that epithelial cell NF-κB also contributes to the exacerbation of infectious colitis. To test this hypothesis, compartmentalized classical NF-κB defective mice, via the deletion of IKKβ in either intestinal epithelial cells (IKKβΔIEC) or myeloid-derived cells (IKKβΔMY), and wild type (WT) mice were challenged with C. rodentium. Both pathogen colonization and colonic histopathology were significantly reduced in IKKβ-deficient mice compared to WT mice. Interestingly, colonic IL-10, RegIIIγ, TNF-α, and iNOS gene expression were increased in IKKβ-deficient mice in the absence of bacterial challenge. This was associated with increased p52, which is involved with activation of NF-κβ through the alternative pathway. IKKβ-deficient mice also had distinct differences in colonic tissue-associated and luminal microbiome that may confer protection against C. rodentium. Taken together, these data demonstrate that classical NF-κB signaling can lead to enhanced enteric pathogen colonization and resulting colonic histopathology.
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Affiliation(s)
- Amy R Mackos
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
| | - Jacob M Allen
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
| | - Eunsoo Kim
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
| | - Chris A Ladaika
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States
| | - Raad Z Gharaibeh
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States.,Bioinformatics Services Division, Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Kannapolis, NC, United States
| | - Cathy Moore
- Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States
| | - Nicola M A Parry
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Prosper N Boyaka
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
| | - Michael T Bailey
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, United States
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27
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Yang H, Yu HB, Bhinder G, Ryz NR, Lee J, Yang H, Fotovati A, Gibson DL, Turvey SE, Reid GS, Vallance BA. TLR9 limits enteric antimicrobial responses and promotes microbiota-based colonisation resistance during Citrobacter rodentium infection. Cell Microbiol 2019; 21:e13026. [PMID: 30893495 DOI: 10.1111/cmi.13026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 02/15/2019] [Accepted: 02/27/2019] [Indexed: 12/18/2022]
Abstract
Mammalian cells express an array of toll-like receptors to detect and respond to microbial pathogens, including enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC). These clinically important attaching and effacing (A/E) pathogens infect the apical surface of intestinal epithelial cells, causing inflammation as well as severe diarrheal disease. Because EPEC and EHEC are human-specific, the related murine pathogen Citrobacter rodentium has been widely used to define how hosts defend against A/E pathogens. This study explored the role of TLR9, a receptor that recognises unmethylated CpG dinucleotides present in bacterial DNA, in promoting host defence against C. rodentium. Infected Tlr9-/- mice suffered exaggerated intestinal damage and carried significantly higher (10-100 fold) pathogen burdens in their intestinal tissues as compared with wild type (WT) mice. C. rodentium infection also induced increased antimicrobial responses, as well as hyperactivation of NF-κB signalling in the intestines of Tlr9-/- mice. These changes were associated with accelerated depletion of the intestinal microbiota in Tlr9-/- mice as compared with WT mice. Notably, antibiotic-based depletion of the gut microbiota in WT mice prior to infection increased their susceptibility to the levels seen in Tlr9-/- mice. Our results therefore indicate that TLR9 signalling suppresses intestinal antimicrobial responses, thereby promoting microbiota-mediated colonisation resistance against C. rodentium infection.
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Affiliation(s)
- Hyungjun Yang
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Hong B Yu
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Ganive Bhinder
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Natasha R Ryz
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Julia Lee
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Hong Yang
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Abbas Fotovati
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Deanna L Gibson
- Department of Biology, The Irving K. Barber School of Arts and Sciences, University of British Columbia, Kelowna, British Columbia, Canada
| | - Stuart E Turvey
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Gregor S Reid
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Bruce A Vallance
- Department of Pediatrics, BC Children's Hospital Research Institute and the University of British Columbia, Vancouver, British Columbia, Canada
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28
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Zhao H, Dai X, Han X, Liu A, Bao F, Bai R, Ji Z, Jian M, Ding Z, Abi ME, Chen T, Luo L, Ma M, Tao L. Borrelia burgdorferi basic membrane protein A initiates proinflammatory chemokine storm in THP 1-derived macrophages via the receptors TLR1 and TLR2. Biomed Pharmacother 2019; 115:108874. [PMID: 31003080 DOI: 10.1016/j.biopha.2019.108874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/28/2019] [Accepted: 04/09/2019] [Indexed: 01/01/2023] Open
Abstract
Lyme disease, reffered to as Lyme borreliosis, is a tick-borne zoonotic disease caused by Borrelia burgdorferi spirochetes. Lyme arthritis, the most common, serious and harmful manifestation during the late stages of Lyme disease, is closely associated with the Borrelia burgdorferi basic membrane protein A (BmpA). Chemokines are also reported to have an important role in Lyme arthritis. Toll-like receptors (TLRs) recognize and bind to pathogen-associated molecules which are structurally conserved among microbes, to activate transcriptional events, including cytokine production, inflammation, and tissue damage. We speculated that BmpA could induce a storm of proinflammatory chemokines via TLRs and downstream moleculars, and that TLR1, TLR2, TLR5, TLR6 and the adaptor protein, MyD88, may be involved in this process. We explored this hypothesis using the human monocytic leukemia cell line, THP-1, and recombinant BmpA (rBmpA). Cell surface TLR1 and TLR2 were neutralized using specific antibodies before stimulation with rBmpA and analysis of chemokine secretion using a chemokine chip. Further, the expressions level of the four TLRs and MyD88 were analyzed following stimulation with rBmpA. Stimulation with rBmpA resulted in elevated levels of seven cytokines. Further, TLR1 and TLR2 antibody treated cells exhibited an overall reduction in rBmpA-induced chemokine expression. TLR1, TLR2, and MyD88 expression levels (both mRNA and protein) increased after stimulation with rBmpA. Our data confirm that TLR1, TLR2, and MyD88 are involved in BmpA-induced proinflammatory chemokines, which may be closely involved in Lyme arthritis pathogenesis.
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Affiliation(s)
- Hua Zhao
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Xiting Dai
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Xinlin Han
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Aihua Liu
- Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming 650500, China; Yunnan Province Key Laboratory for Tropical Infectious Diseases in Universities, Kunming Medical University, Kunming 650500, China; The Institute for Tropical Medicine, Kunming Medical University, Kunming 650500, China; Yunnan Demonstration Base of International Science and Technology Cooperation for Tropical Diseases, Kunming 650500, China.
| | - Fukai Bao
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China; Yunnan Province Key Laboratory for Tropical Infectious Diseases in Universities, Kunming Medical University, Kunming 650500, China; The Institute for Tropical Medicine, Kunming Medical University, Kunming 650500, China; Yunnan Demonstration Base of International Science and Technology Cooperation for Tropical Diseases, Kunming 650500, China.
| | - Ruolan Bai
- Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming 650500, China
| | - Zhenhua Ji
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Miaomiao Jian
- Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming 650500, China
| | - Zhe Ding
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Manzama-Esso Abi
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Taigui Chen
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Lisha Luo
- Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming 650500, China
| | - Mingbiao Ma
- Department of Microbiology and Immunology, Kunming Medical University, Kunming 650500, China
| | - Lvyan Tao
- Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming 650500, China
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29
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Kanmani P, Kim H. Functional capabilities of probiotic strains on attenuation of intestinal epithelial cell inflammatory response induced by TLR4 stimuli. Biofactors 2019; 45:223-235. [PMID: 30537409 DOI: 10.1002/biof.1475] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/10/2018] [Accepted: 10/12/2018] [Indexed: 12/28/2022]
Abstract
Intestinal epithelial cells (IECs) respond to intruders and their cellular molecules by displaying inflammatory state that can be abrogated by probiotics. However, the molecular mechanisms underlying the beneficial activity of probiotic strains have yet to be elucidated. This study was conducted to investigate whether probiotic strains have immunoregulatory effects in IECs, and how they respond to bacterial lipopolysaccharide (LPS) in vitro. Caco2 cells were stimulated with LABs and followed by LPS. The expression of different cytokines that involved in toll-like receptor (TLR) signaling was analyzed. Caco2 cells that were exposed to LPS showed upregulated expression of IL-6, CXCL8, CCL2, and BPI that were counteracted by LAB strains through the modulation of TLR negative regulators (A20, Tollip, SIGIRR, and IRAKM), p38 MAPK and p65 NF-κB signaling. Lactobacillus plantarum, L. farciminis, and L. pentosus unveiled better activity as compared to other strains. Moreover, LAB strains were the potent inducers of immunoregulatory cytokines in coculture system. The expression of IL-10 and TGF-β were found to be higher as compared with LPS. Conversely, TNF-α at the protein level was dampened by LAB strains in both the apical and basolateral compartments. Collectively, our results demonstrated that the selected LAB strains exert profound immunoregulatory effects in response to LPS on IECs; however, further studies in vivo and in clinical settings are important to corroborate these effects. © 2018 BioFactors, 45(2):223-235, 2019.
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Affiliation(s)
- Paulraj Kanmani
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University Ilsan Hospital, Goyang, Gyeonggi, Republic of Korea
| | - Hojun Kim
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University Ilsan Hospital, Goyang, Gyeonggi, Republic of Korea
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30
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Mei Y, Liu H. IL-37: An anti-inflammatory cytokine with antitumor functions. Cancer Rep (Hoboken) 2018; 2:e1151. [PMID: 32935478 DOI: 10.1002/cnr2.1151] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 10/26/2018] [Accepted: 10/26/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND IL-37 is a newly identified IL-1 family cytokine. Unlike other members in IL-1 family, IL-37 has been demonstrated to be an anti-inflammatory cytokine in many inflammatory and autoimmune diseases. IL-37 is regarded as a dual-function cytokine as both the extracellular and intracellular IL-37 are biologically functional. Extracellular IL-37 can bind to IL-18Rα and IL-1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL-37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL-37 in tumor development has been extensively studied. RECENT FINDINGS IL-37 has been found to play an antitumor role in various types of tumors, such as non-small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL-37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL-37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti-inflammatory function. We focused on the role of IL-37 in various tumor types and provided the hypothesis regarding the underlying mechanisms. CONCLUSION IL-37 may affect tumor development through multiple mechanisms: (1) IL-37 directly influences tumor cell viability; (2) IL-37 regulates the immune response to promote the antitumor immunity; and (3) IL-37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL-37 in animal models and cancer patients.
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Affiliation(s)
- Yu Mei
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore
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31
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Sham HP, Bazett M, Bosiljcic M, Yang H, Luk B, Law HT, Morampudi V, Yu HB, Pankovich J, Sutcliffe S, Bressler B, Marshall JK, Fedorak RN, Chen J, Jones M, Gunn H, Kalyan S, Vallance BA. Immune Stimulation Using a Gut Microbe-Based Immunotherapy Reduces Disease Pathology and Improves Barrier Function in Ulcerative Colitis. Front Immunol 2018; 9:2211. [PMID: 30319652 PMCID: PMC6170651 DOI: 10.3389/fimmu.2018.02211] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 09/06/2018] [Indexed: 01/17/2023] Open
Abstract
Background: Current ulcerative colitis (UC) treatments are focused on symptom management primarily via immune suppression. Despite the current arsenal of immunosuppressant treatments, the majority of patients with UC still experience disease progression. Importantly, aggressive long-term inhibition of immune function comes with consequent risk, such as serious infections and malignancy. There is thus a recognized need for new, safe and effective treatment strategies for people living with UC that work upstream of managing the symptoms of the disease. The objective of this study was to evaluate a microbial-based treatment, QBECO, that functions to productively activate rather than suppress mucosal immune function as a novel approach to treat UC. Methods: Two established models of experimental colitis, namely chemically-induced DSS colitis and the spontaneous colitis that develops in Muc2 deficient mice, were used to assess whether QBECO treatment could ameliorate gastrointestinal disease. A small exploratory 16-week QBECO open-label trial was subsequently conducted to test the safety and tolerability of this approach and also to determine whether similar improvements in clinical disease and histopathology could be demonstrated in patients with moderate-to-severe UC. Results: QBECO treatment successfully reduced inflammation and promoted mucosal and histological healing in both experimental models and in UC patients. The preclinical models of colitis showed that QBECO ameliorated mucosal pathology, in part by reducing inflammatory cell infiltration, primarily that induced by neutrophils and inflammatory T cells. The most rapid and noticeable change observed in QBECO treated UC patients was a marked reduction in rectal bleeding. Conclusion: Collectively, this work demonstrates for the first time that strategically activating immune function rather than suppressing it, not only does not worsen colitis induced-damage, but may lead to an objective reduction in UC disease pathology.
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Affiliation(s)
| | | | | | - Hyungjun Yang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute (BCCHRI), University of British Columbia, Vancouver, BC, Canada
| | - Beryl Luk
- Qu Biologics Inc., Vancouver, BC, Canada
| | - Hong T Law
- Qu Biologics Inc., Vancouver, BC, Canada.,Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute (BCCHRI), University of British Columbia, Vancouver, BC, Canada
| | - Vijay Morampudi
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute (BCCHRI), University of British Columbia, Vancouver, BC, Canada
| | - Hong B Yu
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute (BCCHRI), University of British Columbia, Vancouver, BC, Canada
| | | | | | - Brian Bressler
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - John K Marshall
- Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - Jenny Chen
- Qu Biologics Inc., Vancouver, BC, Canada
| | | | - Hal Gunn
- Qu Biologics Inc., Vancouver, BC, Canada
| | - Shirin Kalyan
- Qu Biologics Inc., Vancouver, BC, Canada.,Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Bruce A Vallance
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute (BCCHRI), University of British Columbia, Vancouver, BC, Canada
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32
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The Intestinal Epithelium: Central Coordinator of Mucosal Immunity. Trends Immunol 2018; 39:677-696. [DOI: 10.1016/j.it.2018.04.002] [Citation(s) in RCA: 276] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/23/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
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33
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A peculiar case of Campylobacter jejuni attenuated aspartate chemosensory mutant, able to cause pathology and inflammation in avian and murine model animals. Sci Rep 2018; 8:12594. [PMID: 30135522 PMCID: PMC6105663 DOI: 10.1038/s41598-018-30604-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 08/01/2018] [Indexed: 01/25/2023] Open
Abstract
An attenuated Campylobacter jejuni aspartate chemoreceptor ccaA mutant caused gross pathological changes despite reduced colonisation ability in animal models. In chickens, the pathological changes included connective tissue and thickening of the mesenteric fat, as well as the disintegration of the villus tips in the large intestine, whereas in mice, hepatomegaly occurred between 48–72 hours post infection and persisted for the six days of the time course. In addition, there was a significant change in the levels of IL-12p70 in mice infected with the C. jejuni ccaA mutant. CcaA isogenic mutant was hyper-invasive in cell culture and microscopic examination revealed that it had a “run” bias in its “run-and-tumble” chemotactic behaviour. The mutant cells also exhibited lower level of binding to fucosylated and higher binding to sialylated glycan structures in glycan array analysis. This study highlights the importance of investigating phenotypic changes in C. jejuni, as we have shown that specific mutants can cause pathological changes in the host, despite reduction in colonisation potential.
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Stahl M, Tremblay S, Montero M, Vogl W, Xia L, Jacobson K, Menendez A, Vallance BA. The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion. Am J Physiol Gastrointest Liver Physiol 2018; 315:G195-G205. [PMID: 29698056 PMCID: PMC6139647 DOI: 10.1152/ajpgi.00264.2017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Paneth cells are a key subset of secretory epithelial cells found at the base of small intestinal crypts. Unlike intestinal goblet cells, which secrete the mucin Muc2, Paneth cells are best known for producing an array of antimicrobial factors. We unexpectedly identified Muc2 staining localized around Paneth cell granules. Electron microscopy (EM) confirmed an electron lucent halo around these granules, which was lost in Paneth cells from Muc2-deficient (-/-) mice. EM and immunostaining for lysozyme revealed that Muc2-/- Paneth cells contained larger, more densely packed granules within their cytoplasm, and we detected defects in the transcription of key antimicrobial genes in the ileal tissues of Muc2-/- mice. Enteroids derived from the small intestine of wild-type and Muc2-/- mice revealed phenotypic differences in Paneth cells similar to those seen in vivo. Moreover, lysozyme-containing granule release from Muc2-/- enteroid Paneth cells was shown to be impaired. Surprisingly, Paneth cells within human ileal and duodenal tissues were found to be Muc2 negative. Thus Muc2 plays an important role in murine Paneth cells, suggesting links in function with goblet cells; however human Paneth cells lack Muc2, highlighting that caution should be applied when linking murine to human Paneth cell functions. NEW & NOTEWORTHY We demonstrate for the first time that murine Paneth cell granules possess a halo comprised of the mucin Muc2. The presence of Muc2 exerts an impact on Paneth cell granule size and number and facilitates the release and dispersal of antimicrobials into the mucus layer. Interestingly, despite the importance of Muc2 in murine Paneth cell function, our analysis of Muc2 in human intestinal tissues revealed no trace of Muc2 expression by human Paneth cells.
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Affiliation(s)
- Martin Stahl
- 1Division of Gastroenterology, Department of Pediatrics, British Columbia Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Sarah Tremblay
- 2Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, University of Sherbrooke, Quebec, Canada
| | - Marinieve Montero
- 1Division of Gastroenterology, Department of Pediatrics, British Columbia Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Wayne Vogl
- 3Department of Cellular and Physiological Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Lijun Xia
- 4Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Kevan Jacobson
- 1Division of Gastroenterology, Department of Pediatrics, British Columbia Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Alfredo Menendez
- 2Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, University of Sherbrooke, Quebec, Canada
| | - Bruce A. Vallance
- 1Division of Gastroenterology, Department of Pediatrics, British Columbia Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
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Molgora M, Supino D, Mantovani A, Garlanda C. Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8. Immunol Rev 2018; 281:233-247. [PMID: 29247989 DOI: 10.1111/imr.12609] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.
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Affiliation(s)
- Martina Molgora
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Domenico Supino
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Alberto Mantovani
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Italy.,Humanitas University, Pieve Emanuele (Milano), Italy.,The William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Cecilia Garlanda
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Italy.,Humanitas University, Pieve Emanuele (Milano), Italy
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36
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MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium. PLoS Pathog 2017; 13:e1006357. [PMID: 28520792 PMCID: PMC5433783 DOI: 10.1371/journal.ppat.1006357] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 04/18/2017] [Indexed: 12/29/2022] Open
Abstract
MyD88-mediated signaling downstream of Toll-like receptors and the IL-1 receptor family is critically involved in the induction of protective host responses upon infections. Although it is known that MyD88-deficient mice are highly susceptible to a wide range of bacterial infections, the cell type-specific contribution of MyD88 in protecting the host against intestinal bacterial infection is only poorly understood. In order to investigate the importance of MyD88 in specific immune and nonimmune cell types during intestinal infection, we employed a novel murine knock-in model for MyD88 that enables the cell type-specific reactivation of functional MyD88 expression in otherwise MyD88-deficient mice. We report here that functional MyD88 signaling in CD11c+ cells was sufficient to activate intestinal dendritic cells (DC) and to induce the early group 3 innate lymphoid cell (ILC3) response as well as the development of colonic Th17/Th1 cells in response to infection with the intestinal pathogen C. rodentium. In contrast, restricting MyD88 signaling to several other cell types, including macrophages (MO), T cells or ILC3 did not induce efficient intestinal immune responses upon infection. However, we observed that the functional expression of MyD88 in intestinal epithelial cells (IEC) also partially protected the mice during intestinal infection, which was associated with enhanced epithelial barrier integrity and increased expression of the antimicrobial peptide RegIIIγ and the acute phase protein SAA1 by epithelial cells. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium. MyD88-dependent signaling pathways play a critical role in the protective immune response during intestinal infections. However, the significance of MyD88-mediated signaling in specific intestinal immune and nonimmune cell types for the activation of the early innate, adaptive and epithelial host responses upon infection remains poorly understood. Using a novel knock-in mouse model for MyD88, we report here that MyD88 signaling in CD11c+ dendritic cells (DC) is sufficient to activate RORγt+ group 3 innate lymphoid cells (ILC3) as well as Th17/Th1 cells in response to infection with C. rodentium. In contrast, restricting functional MyD88 signaling to several other immune cell types, including macrophages (MO), T cells and ILC3 did not result in intestinal immunity, while expression of MyD88 in intestinal epithelial cells (IEC) mainly enhanced epithelial barrier integrity. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium.
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Liu H, Ge B. Interleukin-37: a new molecular target for host-directed therapy of tuberculosis. Future Microbiol 2017; 12:465-468. [PMID: 28481119 DOI: 10.2217/fmb-2017-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Haipeng Liu
- Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.,Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Baoxue Ge
- Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.,Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
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38
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Milk Fat Globule Membrane Supplementation in Formula Modulates the Neonatal Gut Microbiome and Normalizes Intestinal Development. Sci Rep 2017; 7:45274. [PMID: 28349941 PMCID: PMC5368573 DOI: 10.1038/srep45274] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 02/23/2017] [Indexed: 12/11/2022] Open
Abstract
Breast milk has many beneficial properties and unusual characteristics including a unique fat component, termed milk fat globule membrane (MFGM). While breast milk yields important developmental benefits, there are situations where it is unavailable resulting in a need for formula feeding. Most formulas do not contain MFGM, but derive their lipids from vegetable sources, which differ greatly in size and composition. Here we tested the effects of MFGM supplementation on intestinal development and the microbiome as well as its potential to protect against Clostridium difficile induced colitis. The pup-in-a-cup model was used to deliver either control or MFGM supplemented formula to rats from 5 to 15 days of age; with mother’s milk (MM) reared animals used as controls. While CTL formula yielded significant deficits in intestinal development as compared to MM littermates, addition of MFGM to formula restored intestinal growth, Paneth and goblet cell numbers, and tight junction protein patterns to that of MM pups. Moreover, the gut microbiota of MFGM and MM pups displayed greater similarities than CTL, and proved protective against C. difficile toxin induced inflammation. Our study thus demonstrates that addition of MFGM to formula promotes development of the intestinal epithelium and microbiome and protects against inflammation.
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Abstract
An underlying genetic predisposition to necrotizing enterocolitis (NEC) is increasingly being recognized. Candidate gene or pathway approaches as well as genome-wide approaches are beginning to identify potential pathogenic variants for NEC in premature infants. However, a majority of these studies have not yielded definitive results because of limited sample size and lack of validation. Despite these challenges, understanding the contribution of genetic variation to NEC is important for providing new insights into the pathogenesis of NEC as well as allowing for targeted care of infants with inherent susceptibility. In this review we provide a summary of published genetic association studies in NEC along with defining the challenges and possible future approaches.
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Affiliation(s)
- Alain Cuna
- Division of Neonatology, Department of Pediatrics, Children's Mercy Hospital, University of Missouri-Kansas City, 2401 Gillham Rd, Kansas City, MO 64108
| | - Venkatesh Sampath
- Division of Neonatology, Department of Pediatrics, Children's Mercy Hospital, University of Missouri-Kansas City, 2401 Gillham Rd, Kansas City, MO 64108.
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Stahl M, Graef FA, Vallance BA. Mouse Models for Campylobacter jejuni Colonization and Infection. Methods Mol Biol 2017; 1512:171-188. [PMID: 27885607 DOI: 10.1007/978-1-4939-6536-6_15] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Relevant animal models for Campylobacter jejuni infection have been difficult to establish due to C. jejuni's inability to cause disease in many common animal research models. Fortunately, recent work has proven successful in developing several new and relevant mouse models of C. jejuni infection, including the SIGIRR-deficient mouse strain that develops acute enterocolitis in response to C. jejuni. Here we describe how to properly infect mice with C. jejuni, as well as a number of accompanying histological techniques to aid in studying C. jejuni colonization and infection in mice.
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Affiliation(s)
- Martin Stahl
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, V6H 3V4, Canada
| | - Franziska A Graef
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, V6H 3V4, Canada
| | - Bruce A Vallance
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, V6H 3V4, Canada.
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The Helical Shape of Campylobacter jejuni Promotes In Vivo Pathogenesis by Aiding Transit through Intestinal Mucus and Colonization of Crypts. Infect Immun 2016; 84:3399-3407. [PMID: 27647867 DOI: 10.1128/iai.00751-16] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 09/10/2016] [Indexed: 11/20/2022] Open
Abstract
Campylobacter jejuni is a helix-shaped enteric bacterial pathogen and a common cause of gastroenteritis. We recently developed a mouse model for this human pathogen utilizing the SIGIRR-deficient mouse strain, which exhibits significant intestinal inflammation in response to intestinal C. jejuni infection. In the current study, this mouse model was used to define whether C. jejuni's characteristic helical shape plays a role in its ability to colonize and elicit inflammation in the mouse intestine. Mice were infected with the previously characterized straight-rod Δpgp1 and Δpgp2 mutant strains, along with a newly characterized curved-rod Δ1228 mutant strain. We also compared the resultant infections and pathology to those elicited by the helix-shaped wild-type C. jejuni and complemented strains. Despite displaying wild-type colonization of the intestinal lumen, the straight-rod Δpgp1 and Δpgp2 mutants were essentially nonpathogenic, while all strains with a curved or helical shape retained their expected virulence. Furthermore, analysis of C. jejuni localization within the ceca of infected mice determined that the primary difference between the rod-shaped, nonpathogenic mutants and the helix-shaped, pathogenic strains was the ability to colonize intestinal crypts. Rod-shaped mutants appeared unable to colonize intestinal crypts due to an inability to pass through the intestinal mucus layer to directly contact the epithelium. Together, these results support a critical role for C. jejuni's helical morphology in enabling it to traverse and colonize the mucus-filled intestinal crypts of their host, a necessary step required to trigger intestinal inflammation in response to C. jejuni.
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Yu ZT, Nanthakumar NN, Newburg DS. The Human Milk Oligosaccharide 2'-Fucosyllactose Quenches Campylobacter jejuni-Induced Inflammation in Human Epithelial Cells HEp-2 and HT-29 and in Mouse Intestinal Mucosa. J Nutr 2016; 146:1980-1990. [PMID: 27629573 PMCID: PMC5037868 DOI: 10.3945/jn.116.230706] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 08/09/2016] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Campylobacter jejuni causes diarrhea worldwide; young children are most susceptible. Binding of virulent C. jejuni to the intestinal mucosa is inhibited ex vivo by α1,2-fucosylated carbohydrate moieties, including human milk oligosaccharides (HMOSs). OBJECTIVE The simplest α1,2-fucosylated HMOS structure, 2'-fucosyllactose (2'-FL), can be predominant at ≤5 g/L milk. Although 2'-FL inhibits C. jejuni binding ex vivo and in vivo, the effects of 2'FL on the cell invasion central to C. jejuni pathogenesis have not been tested. Clinical isolates of C. jejuni infect humans, birds, and ferrets, limiting studies on its mammalian pathobiology. METHODS Human epithelial cells HEp-2 and HT-29 infected with the virulent C. jejuni strain 81-176 human isolate were treated with 5 g 2'-FL/L, and the degree of infection and inflammatory response was measured. Four-week-old male wild-type C57BL/6 mice were fed antibiotics to reduce their intestinal microbiota and were inoculated with C. jejuni strain 81-176. The sensitivity of the resulting acute transient enteric infection and immune response to inhibition by 2'-FL ingestion was tested. RESULTS In HEp-2 and HT-29 cells, 2'-FL attenuated 80% of C. jejuni invasion (P < 0.05) and suppressed the release of mucosal proinflammatory signals of interleukin (IL) 8 by 60-70%, IL-1β by 80-90%, and the neutrophil chemoattractant macrophage inflammatory protein 2 (MIP-2) by 50% (P < 0.05). Ingestion of 2'-FL by mice reduced C. jejuni colonization by 80%, weight loss by 5%, histologic features of intestinal inflammation by 50-70%, and induction of inflammatory signaling molecules of the acute-phase mucosal immune response by 50-60% (P < 0.05). This acute model did not induce IL-17 (adaptive T cell response), a chronic response. CONCLUSIONS In human cells in vitro (HEp-2, HT-29) and in a mouse infection model that recapitulated key pathologic features of C. jejuni clinical disease, 2'-FL inhibited pathogenesis and its sequelae. These data strongly support the hypothesis that 2'-FL represents a new class of oral agent for prevention, and potentially for treatment, of specific enteric infectious diseases.
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Affiliation(s)
- Zhuo-Teng Yu
- Department of Biology, Boston College, Chestnut Hill, MA; and
| | - N Nanda Nanthakumar
- Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA
| | - David S Newburg
- Department of Biology, Boston College, Chestnut Hill, MA; and
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The goblet cell-derived mediator RELM-β drives spontaneous colitis in Muc2-deficient mice by promoting commensal microbial dysbiosis. Mucosal Immunol 2016; 9:1218-33. [PMID: 26813339 DOI: 10.1038/mi.2015.140] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 12/13/2015] [Indexed: 02/04/2023]
Abstract
Intestinal goblet cells are potentially key players in controlling susceptibility to ulcerative colitis (UC). Although impaired mucin (Muc2) production by goblet cells increases microbial stimulation of the colonic mucosa, goblet cells secrete other mediators that may influence or promote UC development. Correspondingly, Muc2-deficient ((-/-)) mice develop spontaneous colitis, concurrent with the dramatic upregulation of the goblet cell mediator, resistin-like molecule-beta (RELM-β). Testing RELM-β's role, we generated Muc2(-/-)/Retnlb(-/-) mice, finding that RELM-β deficiency significantly attenuated colitis development and symptoms compared with Muc2(-/-) mice. RELM-β expression in Muc2(-/-) mice strongly induced the production/secretion of the antimicrobial lectin RegIIIβ, that exerted its microbicidal effect predominantly on Gram-positive Lactobacillus species. Compared with Muc2(-/-)/Retnlb(-/-) mice, this worsened intestinal microbial dysbiosis with a selective loss of colonic Lactobacilli spp. in Muc2(-/-) mice. Orally replenishing Muc2(-/-) mice with murine Lactobacillus spp., but not with a probiotic formulation containing several human Lactobacillus spp. (VSL#3), ameliorated their spontaneous colitis in concert with increased production of short-chain fatty acids. These studies demonstrate that the goblet cell mediator RELM-β drives colitis in Muc2(-/-) mice by depleting protective commensal microbes. The ability of selective commensal microbial replacement to ameliorate colitis suggests that personalized bacterial therapy may prove beneficial for treatment of UC.
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44
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Achek A, Yesudhas D, Choi S. Toll-like receptors: promising therapeutic targets for inflammatory diseases. Arch Pharm Res 2016; 39:1032-49. [PMID: 27515048 DOI: 10.1007/s12272-016-0806-9] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/01/2016] [Indexed: 12/19/2022]
Abstract
The health of living organisms is constantly challenged by bacterial and viral threats. The recognition of pathogenic microorganisms by diverse receptors triggers a variety of host defense mechanisms, leading to their eradication. Toll-like receptors (TLRs), which are type I transmembrane proteins, recognize specific signatures of the invading microbes and activate a cascade of downstream signals inducing the secretion of inflammatory cytokines, chemokines, and type I interferons. The TLR response not only counteracts the pathogens but also initiates and shapes the adaptive immune response. Under normal conditions, inflammation is downregulated after the removal of the pathogen and cellular debris. However, a dysfunctional TLR-mediated response maintains a chronic inflammatory state and leads to local and systemic deleterious effects in host cells and tissues. Such inappropriate TLR response has been attributed to the development and progression of multiple diseases such as cancer, autoimmune, and inflammatory diseases. In this review, we discuss the emerging role of TLRs in the pathogenesis of inflammatory diseases and how targeting of TLRs offers a promising therapeutic strategy for the prevention and treatment of various inflammatory diseases. Additionally, we highlight a number of TLR-targeting agents that are in the developmental stage or in clinical trials.
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Affiliation(s)
- Asma Achek
- Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea
| | - Dhanusha Yesudhas
- Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
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Bonecchi R, Garlanda C, Mantovani A, Riva F. Cytokine decoy and scavenger receptors as key regulators of immunity and inflammation. Cytokine 2016; 87:37-45. [PMID: 27498604 DOI: 10.1016/j.cyto.2016.06.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 06/17/2016] [Indexed: 12/16/2022]
Abstract
IL-1R2 was the first decoy receptor to be described. Subsequently receptors which act as pure decoys or scavengers or trigger dampening of cytokine signaling have been described for cytokines and chemokines. Here we review the current understanding of the mode of action and significance in pathology of the chemokine atypical receptor ACKR2, the IL-1 decoy receptor IL-1R2 and the atypical IL-1 receptor family IL-1R8. Decoy and scavenger receptors with no or atypical signaling have emerged as a general strategy conserved in evolution to tune the action of cytokines, chemokines and growth factors.
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Affiliation(s)
- Raffaella Bonecchi
- Istituto Clinico Humanitas IRCCS, via Manzoni 113, 20089 Rozzano, Italy; Humanitas University, via Manzoni 113, 20089 Rozzano, Italy
| | - Cecilia Garlanda
- Istituto Clinico Humanitas IRCCS, via Manzoni 113, 20089 Rozzano, Italy
| | - Alberto Mantovani
- Istituto Clinico Humanitas IRCCS, via Manzoni 113, 20089 Rozzano, Italy; Humanitas University, via Manzoni 113, 20089 Rozzano, Italy.
| | - Federica Riva
- Department of Animal Pathology, Faculty of Veterinary Medicine, University of Milan, Italy
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46
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Abstract
Innate immune responses are key to maintain adequate host-microbial interactions. However, those signals are needed to efficiently trigger rapid and targeted antimicrobial responses in case of pathogen encounter. Several molecules have evolved to regulate intensity and coordinate signaling to avoid detrimental consequences to the host. Regulation can occur at the cell surface, within the cytoplasm, and at the transcriptional level. Innate immune regulation seems to be equally important than stimulation, as disruption of immunoregulatory molecules modulates the risk for several diseases. This is the case for colitis and inflammatory bowel disease but also colorectal cancer and intestinal infections. In this review, we recapitulate the molecular mechanisms underlying regulation of innate immune signals and mention their implications in several disease states including inflammatory bowel disease.
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47
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Feng W, Gu YF, Nie L, Guo DY, Xiang LX, Shao JZ. Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation. THE JOURNAL OF IMMUNOLOGY 2016; 197:151-67. [PMID: 27206770 DOI: 10.4049/jimmunol.1502334] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 05/02/2016] [Indexed: 12/20/2022]
Abstract
Single Ig IL-1R-related molecule (SIGIRR, also called IL-1R8 or Toll/IL-1R [TIR]8), a negative regulator for Toll/IL-1R signaling, plays critical roles in innate immunity and various diseases in mammals. However, the occurrence of this molecule in ancient vertebrates and its function in liver homeostasis and disorders remain poorly understood. In this study, we identified a SIGIRR homology from zebrafish (Danio rerio [DrSIGIRR]) by using a number of conserved structural and functional hallmarks to its mammalian counterparts. DrSIGIRR was highly expressed in the liver. Ablation of DrSIGIRR by lentivirus-delivered small interfering RNA in the liver significantly enhanced hepatic inflammation in response to polyinosinic-polycytidylic acid [poly(I:C)] stimulation, as shown by the upregulation of inflammatory cytokines and increased histological disorders. In contrast, depletion of TIR domain-containing adaptor inducing IFN-β (TRIF) or administration of TRIF signaling inhibitor extremely abrogated the poly(I:C)-induced hepatic inflammation. Aided by the zebrafish embryo model, overexpression of DrSIGIRR in vivo significantly inhibited the poly(I:C)- and TRIF-induced NF-κB activations; however, knockdown of DrSIGIRR promoted such activations. Furthermore, pull-down and Duolink in situ proximity ligation assay assays showed that DrSIGIRR can interact with the TRIF protein. Results suggest that DrSIGIRR plays an inhibitory role in TRIF-mediated inflammatory reactions by competitive recruitment of the TRIF adaptor protein from its TLR3/TLR22 receptor. To our knowledge, this study is the first to report a functional SIGIRR homolog that existed in a lower vertebrate. This molecule is essential to establish liver homeostasis under inflammatory stimuli. Overall, the results will enrich the current knowledge about SIGIRR-mediated immunity and disorders in the liver.
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Affiliation(s)
- Wei Feng
- College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and
| | - Yi-Feng Gu
- College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and
| | - Li Nie
- College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and
| | - Dong-Yang Guo
- College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and
| | - Li-Xin Xiang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and
| | - Jian-Zhong Shao
- College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266200, People's Republic of China
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Molgora M, Barajon I, Mantovani A, Garlanda C. Regulatory Role of IL-1R8 in Immunity and Disease. Front Immunol 2016; 7:149. [PMID: 27148268 PMCID: PMC4837151 DOI: 10.3389/fimmu.2016.00149] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 04/05/2016] [Indexed: 12/12/2022] Open
Abstract
Interleukin-1 receptor family members (ILRs) and toll-like receptors (TLRs) are characterized by the presence of a conserved intracellular domain and the toll-IL-1resistance (TIR) domain and are key players in immunity and inflammation. ILR and TLR signaling is tightly regulated at different levels. All cell types of the innate immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R8, also known as TIR8 or SIGIRR, is a fringe member of the ILR family and acts as a negative regulator of ILR and TLR signaling, which dampens ILR- and TLR-mediated cell activation. IL-1R8 is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R8, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation to autoimmunity and cancer-related inflammation.
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Affiliation(s)
- Martina Molgora
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center , Rozzano , Italy
| | | | - Alberto Mantovani
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Italy; Humanitas University, Rozzano, Italy
| | - Cecilia Garlanda
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center , Rozzano , Italy
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Crosstalk between microbiota, pathogens and the innate immune responses. Int J Med Microbiol 2016; 306:257-265. [PMID: 26996809 DOI: 10.1016/j.ijmm.2016.03.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/02/2016] [Accepted: 03/03/2016] [Indexed: 02/07/2023] Open
Abstract
Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis.
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Ryz NR, Lochner A, Bhullar K, Ma C, Huang T, Bhinder G, Bosman E, Wu X, Innis SM, Jacobson K, Vallance BA. Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases susceptibility to Citrobacter rodentium-induced colitis. Am J Physiol Gastrointest Liver Physiol 2015; 309:G730-42. [PMID: 26336925 PMCID: PMC4628967 DOI: 10.1152/ajpgi.00006.2015] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 08/27/2015] [Indexed: 01/31/2023]
Abstract
Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to increase risk of bacterial infections, the importance of vitamin D on host defense against intestinal bacterial pathogens is currently unclear since injection of the active form of vitamin D, 1,25(OH)2D3, increased susceptibility to the enteric bacterial pathogen Citrobacter rodentium by suppressing key immune/inflammatory factors. To further characterize the role of vitamin D during bacteria-induced colitis, we fed weanling mice either vitamin D3-deficient or vitamin D3-sufficient diets for 5 wk and then challenged them with C. rodentium. Vitamin D3-deficient mice lost significantly more body weight, carried higher C. rodentium burdens, and developed worsened histological damage. Vitamin D3-deficient mice also suffered greater bacterial translocation to extra-intestinal tissues, including mesenteric lymph nodes, spleen, and liver. Intestinal tissues of infected vitamin D3-deficient mice displayed increased inflammatory cell infiltrates as well as significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, TGF-β, IL-17A, and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these exaggerated inflammatory responses accelerated the loss of commensal microbes and were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Overall, these studies show that dietary-induced vitamin D deficiency exacerbates intestinal inflammatory responses to infection, also impairing host defense.
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Affiliation(s)
- Natasha R. Ryz
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Arion Lochner
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Kirandeep Bhullar
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Caixia Ma
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Tina Huang
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Ganive Bhinder
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Else Bosman
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Xiujuan Wu
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Sheila M. Innis
- 2Division of Neonatology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kevan Jacobson
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Bruce A. Vallance
- 1Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and
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