1
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Huysentruyt J, Steels W, Ruiz Pérez M, Verstraeten B, Divert T, Flies K, Lemeire K, Takahashi N, De Bruyn E, Joossens M, Brown AS, Lambrecht BN, Declercq W, Vanden Berghe T, Maelfait J, Vandenabeele P, Tougaard P. RIPK1 ablation in T cells results in spontaneous enteropathy and TNF-driven villus atrophy. EMBO Rep 2025; 26:2654-2682. [PMID: 40307618 PMCID: PMC12117051 DOI: 10.1038/s44319-025-00441-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 03/11/2025] [Accepted: 03/18/2025] [Indexed: 05/02/2025] Open
Abstract
RIPK1 is a crucial regulator of cell survival, inflammation and cell death. Human RIPK1 deficiency leads to early-onset intestinal inflammation and peripheral T cell imbalance, though its role in αβT cell-mediated intestinal homeostasis remains unclear. In this study, we demonstrate that mice with RIPK1 ablation in conventional αβT cells (Ripk1ΔCD4) developed a severe small intestinal pathology characterized by small intestinal elongation, crypt hyperplasia, and duodenum-specific villus atrophy. Using mixed bone marrow chimeras reveals a survival disadvantage of αβT cells compared to γδT cells in the small intestine. Broad-spectrum antibiotic treatment ameliorates crypt hyperplasia and prevents intestinal elongation, though villus atrophy persists. Conversely, crossing Ripk1ΔCD4 with TNF receptor 1 Tnfr1-/- knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of Ripk1∆CD4 and Casp8∆CD4 fully rescues intestinal pathology, revealing that αβT cell apoptosis in Ripk1∆CD4 drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of αβT cells is essential for proximal small intestinal homeostasis. In Ripk1∆CD4 mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.
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Affiliation(s)
- Jelle Huysentruyt
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Wolf Steels
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Mario Ruiz Pérez
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Bruno Verstraeten
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Tatyana Divert
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kayleigh Flies
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kelly Lemeire
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Nozomi Takahashi
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Elke De Bruyn
- Laboratory of Microbiology, Department of Biochemistry and Microbiology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Marie Joossens
- Laboratory of Microbiology, Department of Biochemistry and Microbiology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Andrew S Brown
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Bart N Lambrecht
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Wim Declercq
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Jonathan Maelfait
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
| | - Peter Tougaard
- VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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2
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Wang J, Wu Y, Yang J, Ying S, Luo H, Zha L, Li Q. Xylooligosaccharide and Akkermansia muciniphila synergistically ameliorate insulin resistance by reshaping gut microbiota, improving intestinal barrier and regulating NKG2D/NKG2DL signaling in gestational diabetes mellitus mice. Food Res Int 2025; 201:115634. [PMID: 39849761 DOI: 10.1016/j.foodres.2024.115634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/30/2024] [Accepted: 12/28/2024] [Indexed: 01/25/2025]
Abstract
Xylooligosaccharides (XOS) ameliorate insulin resistance (IR) in gestational diabetes mellitus (GDM) probably by propagating Akkermansia muciniphila (Akk). This study aimed to investigate the effects and mechanisms of XOS, Akk and combination on IR in GDM mice/pseudo-germ-free (PGF) mice. Female mice were fed with AIN-93 (n = 19) and high fat diet (HFD) (n = 206). After 4 weeks, HFD-fed mice were further allotted to HFD, GDM, GDM + XOS, GDM + Akk, GDM + XOS + Akk, GDM + PGF, GDM + PGF + XOS, GDM + PGF + Akk, and GDM + PGF + XOS + Akk groups (n ≥ 19). GDM was induced by intraperitoneally injecting streptozotocin and PGF was established by intragastrically administrating antibiotic cocktails. XOS (500 mg/kg·BW) or/and Akk (4 × 108 CFU) were gavaged once a day for 10 days. Fasting blood glucose (FBG), insulin, oral glucose tolerance test (OGTT) and insulin signaling pathway were determined. Gut microbiota were detected by 16S rRNA sequencing and absolute quantities of Akk by qRT-PCR. Intestinal tissues were stained by Hematoxylin-Eosin and Periodic acid-Schiff-Alcian blue staining. Occludin and Zonula occludens-1 (ZO-1) in intestine, Natural killer group 2 member D (NKG2D) on intestinal epithelial lymphocytes (IELs) and NKG2D ligands (NKG2DL) on intestinal epithelial cells (IECs) were detected by Western blotting. In GDM mice, XOS, Akk and XOS + Akk reduced (p < 0.05) the area under the curve of OGTT (AUC), insulin and homeostasis model assessment of insulin resistance (HOMA-IR), and increased (p < 0.05) protein kinase B (Akt) phosphorylation in liver and insulin receptor substrate 1 (IRS-1) phosphorylation in muscle. Furthermore, XOS + Akk reduced (p < 0.05) FBG and increased (p < 0.05) Akt phosphorylation in muscle and IRS-1 phosphorylation in liver. XOS, Akk and XOS + Akk reshaped gut microbiota with XOS + Akk exhibiting the greatest effectiveness. XOS increased (p < 0.05) Akk and clearance of gut microbiota abolished such effect. XOS, Akk and XOS + Akk reduced (p < 0.05) the small intestine Chiu's score and the colon Dieleman's scores, increased (p < 0.05) ZO-1 and Occludin, and reduced (p < 0.05) NKG2D on IELs and NKG2DLs (H60, MULT-1, Rae-1ε) on IECs. Moreover, XOS + Akk reduced (p < 0.05) MULT-1 in duodenum. Collectively, XOS and Akk synergistically ameliorate IR by reshaping gut microbiota, improving intestinal barrier and regulating NKG2D/NKG2DL signaling in GDM mice.
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Affiliation(s)
- Jiexian Wang
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China
| | - Yanhua Wu
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China; Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, 1838. Guangzhou Avenue North, Guangzhou 510515, Guangdong, PR China
| | - Junyi Yang
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China; Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, 1838. Guangzhou Avenue North, Guangzhou 510515, Guangdong, PR China
| | - Shihao Ying
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China; Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, 1838. Guangzhou Avenue North, Guangzhou 510515, Guangdong, PR China
| | - Huiyu Luo
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China
| | - Qing Li
- Department of Nutrition and Food Hygiene, NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1026. Shatai South Road, Guangzhou 510515, Guangdong, PR China; Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, 1838. Guangzhou Avenue North, Guangzhou 510515, Guangdong, PR China.
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3
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Hada A, Xiao Z. Ligands for Intestinal Intraepithelial T Lymphocytes in Health and Disease. Pathogens 2025; 14:109. [PMID: 40005486 PMCID: PMC11858322 DOI: 10.3390/pathogens14020109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
The intestinal tract is constantly exposed to a diverse mixture of luminal antigens, such as those derived from commensals, dietary substances, and potential pathogens. It also serves as a primary route of entry for pathogens. At the forefront of this intestinal defense is a single layer of epithelial cells that forms a critical barrier between the gastrointestinal (GI) lumen and the underlying host tissue. The intestinal intraepithelial T lymphocytes (T-IELs), one of the most abundant lymphocyte populations in the body, play a crucial role in actively surveilling and maintaining the integrity of this barrier by tolerating non-harmful factors such as commensal microbiota and dietary components, promoting epithelial turnover and renewal while also defending against pathogens. This immune balance is maintained through interactions between ligands in the GI microenvironment and receptors on T-IELs. This review provides a detailed examination of the ligands present in the intestinal epithelia and the corresponding receptors expressed on T-IELs, including T cell receptors (TCRs) and non-TCRs, as well as how these ligand-receptor interactions influence T-IEL functions under both steady-state and pathological conditions. By understanding these engagements, we aim to shed light on the mechanisms that govern T-IEL activities within the GI microenvironment. This knowledge may help in developing strategies to target GI ligands and modulate T-IEL receptor expression, offering precise approaches for treating intestinal disorders.
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Affiliation(s)
| | - Zhengguo Xiao
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA;
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4
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Yomogida K, Trsan T, Sudan R, Rodrigues PF, Ulezko Antonova A, Ingle H, Luccia BD, Collins PL, Cella M, Gilfillan S, Baldridge MT, Oltz EM, Colonna M. The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes. Nat Immunol 2024; 25:77-87. [PMID: 38049581 PMCID: PMC11835375 DOI: 10.1038/s41590-023-01693-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 10/27/2023] [Indexed: 12/06/2023]
Abstract
Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3-/- CD8αα+ IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3-/- and Ikzf3+/+ IELs showed an amplified effector machinery in Ikzf3-/- CD8αα+ IELs compared to Ikzf3+/+ counterparts. Ikzf3-/- CD8αα+ IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.
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Affiliation(s)
- Kentaro Yomogida
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, CO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Tihana Trsan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Raki Sudan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Patrick F Rodrigues
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Alina Ulezko Antonova
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Harshad Ingle
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, USA
| | - Blanda Di Luccia
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
| | - Patrick L Collins
- Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA
| | - Marina Cella
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Susan Gilfillan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Megan T Baldridge
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, USA
| | - Eugene M Oltz
- Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
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5
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Teng M, Zhao X, Zhou L, Yan H, Zhao L, Sun J, Li Y, Zhu W, Wu F. An integrated analysis of the fecal metabolome and metagenome reveals the distinct effects of differentially charged nanoplastics on the gut microbiota-associated metabolites in mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 906:167287. [PMID: 37748599 DOI: 10.1016/j.scitotenv.2023.167287] [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: 06/12/2023] [Revised: 09/14/2023] [Accepted: 09/20/2023] [Indexed: 09/27/2023]
Abstract
Whether nanoplastics with differential charges cause intestinal impairment via distinct mechanisms remains unclear. We investigated the relationship between fecal metabolites and the gut microbiome, and potential biomarkers thereof, in mice following exposure to differentially charged polystyrene nanoplastics (PS-NPs). Metagenomic analysis revealed that exposure to differentially charged PS-NPs resulted in alterations in the abundances of Bilophila_wadsworthia, Helicobacter apodemus, and Helicobacter typhlonius. A total of 237 fecal metabolites were significantly altered in mice that exhibited intestinal impairment, and these included 10 gut microbiota-related fecal metabolites that accurately discriminated impaired intestinal samples from the control. Additionally, the specific gut microbiome-related fecal metabolite-based model approach for the prediction of intestinal impairment in mice had an area under the curve (AUC) of 1.0 in the PS (without charge) group, an AUC of 0.94 in the PS-NH2 (positive charge) group, and an AUC of 0.86 in the PS-COOH (negative charge) group. Thus, the model showed promising evaluable accuracy for the prediction of intestinal impairment induced by nanoplastics in a charge-specific manner. Our study demonstrates that the fecal metabolome of mice with intestinal impairment following exposure to differentially charged nanoplastics is associated with changes in the gut microbiome. The identified biomarkers have potential application for the detection of intestinal impairment after exposure to negative, positive, or noncharged nanomaterials.
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Affiliation(s)
- Miaomiao Teng
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Xiaoli Zhao
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
| | - Lingfeng Zhou
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Hong Yan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, USA
| | - Lihui Zhao
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Jiaqi Sun
- School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Yunxia Li
- School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Wentao Zhu
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
| | - Fengchang Wu
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
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6
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Calabrese DR, Tsao T, Magnen M, Valet C, Gao Y, Mallavia B, Tian JJ, Aminian EA, Wang KM, Shemesh A, Punzalan EB, Sarma A, Calfee CS, Christenson SA, Langelier CR, Hays SR, Golden JA, Leard LE, Kleinhenz ME, Kolaitis NA, Shah R, Venado A, Lanier LL, Greenland JR, Sayah DM, Ardehali A, Kukreja J, Weigt SS, Belperio JA, Singer JP, Looney MR. NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes. JCI Insight 2022; 7:e164603. [PMID: 36346670 PMCID: PMC9869973 DOI: 10.1172/jci.insight.164603] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.
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Affiliation(s)
- Daniel R. Calabrese
- Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Tasha Tsao
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Mélia Magnen
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Colin Valet
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Ying Gao
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Beñat Mallavia
- Department of Medicine, UCSF, San Francisco, California, USA
| | | | | | - Kristin M. Wang
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Avishai Shemesh
- Department of Medicine, UCSF, San Francisco, California, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
| | | | - Aartik Sarma
- Department of Medicine, UCSF, San Francisco, California, USA
| | | | | | | | - Steven R. Hays
- Department of Medicine, UCSF, San Francisco, California, USA
| | | | | | | | | | - Rupal Shah
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Aida Venado
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Lewis L. Lanier
- Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
- Department of Microbiology and Immunology and
| | - John R. Greenland
- Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
- Department of Medicine, UCSF, San Francisco, California, USA
| | - David M. Sayah
- Department of Medicine, UCLA, Los Angeles, California, USA
| | - Abbas Ardehali
- Department of Medicine, UCLA, Los Angeles, California, USA
| | | | | | | | | | - Mark R. Looney
- Department of Medicine, UCSF, San Francisco, California, USA
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7
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Dong Y, Liu J, Lu N, Zhang C. Enterovirus 71 Antagonizes Antiviral Effects of Type III Interferon and Evades the Clearance of Intestinal Intraepithelial Lymphocytes. Front Microbiol 2022; 12:806084. [PMID: 35185830 PMCID: PMC8848745 DOI: 10.3389/fmicb.2021.806084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 11/16/2021] [Indexed: 11/29/2022] Open
Abstract
Enterovirus 71 (EV71) is the major pathogen causing severe neurological complications and hand, foot, and mouth disease. The intestinal mucosal immune system has a complete immune response and immune regulation mechanism, consisting of densely arranged monolayer intestinal epithelial cells (IECs) and intestinal intraepithelial lymphocytes (iIELs) distributed among the IECs, which constitute the first line of intestinal mucosa against infection of foreign pathogens. As an enterovirus, EV71 is transmitted by the intestinal tract; however, the mechanisms it uses to evade the immunosurveillance of the intestinal mucosal immune system are still incompletely clarified. The present study investigated how EV71 evades from recognizing and eliminating IECs, iIELs, and iNK cells. We found that EV71 infection induced a higher level of type III interferons (IFN-λ) than type I interferons (IFN-β) in IECs, and the addition of IFN-λ markedly restricted EV71 replication in IECs. These results indicate that IFN-λ plays a more important role in anti-EV71 intestinal infection. However, EV71 infection could markedly attenuate the antiviral responses of IFN-λ. Mechanistically, 2A protease (2Apro) and 3C protease (3Cpro) of EV71 inhibited the IFN-λ production and IFN-λ receptor expression and further decreased the response of IECs to IFN-λ. In addition, we found that EV71-infected IECs were less susceptible to the lysis of intestinal NK (iNK) cells and CD3+iIELs. We revealed that the viral 2Apro and 3Cpro could significantly reduce the expression of the ligands of natural killer group 2D (NKG2D) and promote the expression of PD-L1 on IECs, rendering them to evade the recognition and killing of iNK and CD3+iIELs. These results provide novel evasion mechanisms of EV71 from intestinal mucosal innate immunity and may give new insights into antiviral therapy.
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Affiliation(s)
- Yuanmin Dong
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing Liu
- Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
| | - Nan Lu
- Institute of Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Cai Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
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8
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Villena J, Li C, Vizoso-Pinto MG, Sacur J, Ren L, Kitazawa H. Lactiplantibacillus plantarum as a Potential Adjuvant and Delivery System for the Development of SARS-CoV-2 Oral Vaccines. Microorganisms 2021; 9:683. [PMID: 33810287 PMCID: PMC8067309 DOI: 10.3390/microorganisms9040683] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/18/2021] [Accepted: 03/24/2021] [Indexed: 01/08/2023] Open
Abstract
The most important characteristics regarding the mucosal infection and immune responses against the Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) as well as the current vaccines against coronavirus disease 2019 (COVID-19) in development or use are revised to emphasize the opportunity for lactic acid bacteria (LAB)-based vaccines to offer a valid alternative in the fight against this disease. In addition, this article revises the knowledge on: (a) the cellular and molecular mechanisms involved in the improvement of mucosal antiviral defenses by beneficial Lactiplantibacillus plantarum strains, (b) the systems for the expression of heterologous proteins in L. plantarum and (c) the successful expressions of viral antigens in L. plantarum that were capable of inducing protective immune responses in the gut and the respiratory tract after their oral administration. The ability of L. plantarum to express viral antigens, including the spike protein of SARS-CoV-2 and its capacity to differentially modulate the innate and adaptive immune responses in both the intestinal and respiratory mucosa after its oral administration, indicates the potential of this LAB to be used in the development of a mucosal COVID-19 vaccine.
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Affiliation(s)
- Julio Villena
- Reference Centre for Lactobacilli (CERELA-CONICET), Laboratory of Immunobiotechnology, Tucuman CP4000, Argentina
- Laboratory of Animal Products Chemistry, Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Chang Li
- Research Unit of Key Technologies for Prevention and Control of Virus Zoonoses, Chinese Academy of Medical Sciences, Military Veterinary Institute, Academy of Military Medical Sciences, Changchun 130122, China;
| | - Maria Guadalupe Vizoso-Pinto
- Infection Biology Laboratory, Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, Tucuman CP4000, Argentina; (M.G.V.-P.); (J.S.)
| | - Jacinto Sacur
- Infection Biology Laboratory, Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, Tucuman CP4000, Argentina; (M.G.V.-P.); (J.S.)
| | - Linzhu Ren
- College of Animal Sciences, Key Lab for Zoonoses Research, Ministry of Education, Jilin University, Changchun 130062, China
| | - Haruki Kitazawa
- Laboratory of Animal Products Chemistry, Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
- International Education and Research Center for Food Agricultural Immunology, Livestock Immunology Unit, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
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9
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D'Avino P, Serena G, Kenyon V, Fasano A. An updated overview on celiac disease: from immuno-pathogenesis and immuno-genetics to therapeutic implications. Expert Rev Clin Immunol 2021; 17:269-284. [PMID: 33472447 DOI: 10.1080/1744666x.2021.1880320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Celiac disease (CD) is an autoimmune enteropathy triggered by ingestion of gluten. While presenting many similarities with other autoimmune diseases, celiac disease is unique in that the external trigger, gluten, and the genetic background necessary for disease development (HLA DQ2/DQ8) are well described. The prevalence of celiac disease is dramatically increasing over the years and new epidemiologic data show changes regarding age of onset and symptoms. A better understanding of CD-pathogenesis is fundamental to highlight the reasons of this rise of celiac diagnoses. AREAS COVERED In this review we describe CD-pathogenesis by dissecting all the components necessary to lose tolerance to gluten (ingestion of gluten, genetic predisposition, loss of barrier function and immune response). Additionally, we also highlight the role that microbiome plays in celiac disease as well as new proposed therapies and experimental tools. EXPERT OPINION Prevalence of autoimmune diseases is increasing around the world. As a result, modern society is strongly impacted by a social and economic burden. Given the unique characteristics of celiac disease, a better understanding of its pathogenesis and the factors that contribute to it may shed light on other autoimmune diseases for which external trigger and genetic background are not known.
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Affiliation(s)
- Paolo D'Avino
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Vita-Salute San Raffaele University, Milan, Italy
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Victoria Kenyon
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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10
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Vandereyken M, James OJ, Swamy M. Mechanisms of activation of innate-like intraepithelial T lymphocytes. Mucosal Immunol 2020; 13:721-731. [PMID: 32415229 PMCID: PMC7434593 DOI: 10.1038/s41385-020-0294-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 04/09/2020] [Accepted: 04/11/2020] [Indexed: 02/04/2023]
Abstract
Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential.
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Affiliation(s)
- Maud Vandereyken
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Olivia J James
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Mahima Swamy
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
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11
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Mizuno H, Arce L, Tomotsune K, Albarracin L, Funabashi R, Vera D, Islam MA, Vizoso-Pinto MG, Takahashi H, Sasaki Y, Kitazawa H, Villena J. Lipoteichoic Acid Is Involved in the Ability of the Immunobiotic Strain Lactobacillus plantarum CRL1506 to Modulate the Intestinal Antiviral Innate Immunity Triggered by TLR3 Activation. Front Immunol 2020; 11:571. [PMID: 32328062 PMCID: PMC7161159 DOI: 10.3389/fimmu.2020.00571] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Accepted: 03/12/2020] [Indexed: 12/14/2022] Open
Abstract
Studies have demonstrated that lipoteichoic acid (LTA) is involved in the immunomodulatory properties of some immunobiotic lactobacilli. The aim of this work was to evaluate whether LTA contributes to the capacity of Lactobacillus plantarum CRL1506 in modulating the intestinal innate antiviral immune response. A D-alanyl-lipoteichoic acid biosynthesis protein (dltD) knockout CRL1506 strain (L. plantarumΔdltD) was obtained, and its ability to modulate Toll-like receptor (TLR)-3-mediated immune response was evaluated in vitro in porcine intestinal epithelial (PIE) cells and in vivo in Balb/c mice. Wild-type (WT) CRL1506 (L. plantarum WT) was used as positive control. The challenge of PIE cells with the TLR3 agonist poly(I:C) significantly increased interferon (IFN)-β, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 expressions. PIE cells pretreated with L. plantarumΔdltD or L. plantarum WT showed higher levels of IFN-β while only L. plantarum WT significantly reduced the expression of IL-6 and MCP-1 when compared with poly(I:C)-treated control cells. The oral administration of L. plantarum WT to mice prior the intraperitoneal injection of poly(I:C) significantly increased IFN-β and IL-10 and reduced intraepithelial lymphocytes (CD3+NK1.1+CD8αα+) and pro-inflammatory mediators (TNF-α, IL-6, and IL-15) in the intestinal mucosa. Similar to the WT strain, L. plantarumΔdltD-treated mice showed enhanced levels of IFN-β after poly(I:C) challenge. However, treatment of mice with L. plantarumΔdltD was not able to increase IL-10 or reduce CD3+NK1.1+CD8αα+ cells, TNF-α, IL-6, or IL-15 in the intestine. These results indicate that LTA would be a key molecule in the anti-inflammatory effect induced by the CRL1506 strain in the context of TLR3-mediated inflammation.
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Affiliation(s)
- Hiroya Mizuno
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Lorena Arce
- Infection Biology Laboratory, Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, Tucumán, Argentina
| | - Kae Tomotsune
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Leonardo Albarracin
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina
| | - Ryutaro Funabashi
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Daniela Vera
- Infection Biology Laboratory, Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, Tucumán, Argentina.,Laboratorio de Ciencias Básicas Or. Genética, Facultad de Medicina de la Universidad Nacional de Tucuman, Tucumán, Argentina
| | - Md Aminul Islam
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Department of Medicine, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Maria Guadalupe Vizoso-Pinto
- Infection Biology Laboratory, Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, Tucumán, Argentina.,Laboratorio de Ciencias Básicas Or. Genética, Facultad de Medicina de la Universidad Nacional de Tucuman, Tucumán, Argentina
| | - Hideki Takahashi
- Plant Immunology Unit, International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Yasuko Sasaki
- Graduate School of Agriculture, Meiji University, Kawasaki, Japan
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Julio Villena
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina
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12
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Albarracin L, Garcia-Castillo V, Masumizu Y, Indo Y, Islam MA, Suda Y, Garcia-Cancino A, Aso H, Takahashi H, Kitazawa H, Villena J. Efficient Selection of New Immunobiotic Strains With Antiviral Effects in Local and Distal Mucosal Sites by Using Porcine Intestinal Epitheliocytes. Front Immunol 2020; 11:543. [PMID: 32322251 PMCID: PMC7156603 DOI: 10.3389/fimmu.2020.00543] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/10/2020] [Indexed: 12/31/2022] Open
Abstract
Previously, we evaluated the effect of the immunobiotic strain Lactobacillus rhamnosus CRL1505 on the transcriptomic response of porcine intestinal epithelial (PIE) cells triggered by the challenge with the Toll-like receptor 3 (TLR-3) agonist poly(I:C) and successfully identified a group of genes that can be used as prospective biomarkers for the screening of new antiviral immunobiotics. In this work, several strains of lactobacilli were evaluated according to their ability to modulate the expression of IFNα, IFNβ, RIG1, TLR3, OAS1, RNASEL, MX2, A20, CXCL5, CCL4, IL-15, SELL, SELE, EPCAM, PTGS2, PTEGES, and PTGER4 in PIE cells after the stimulation with poly(I:C). Comparative analysis of transcripts variations revealed that one of the studied bacteria, Lactobacillus plantarum MPL16, clustered together with the CRL1505 strain, indicating a similar immunomodulatory potential. Two sets of in vivo experiments in Balb/c mice were performed to evaluate L. plantarum MPL16 immunomodulatory activities. Orally administered MPL16 prior intraperitoneal injection of poly(I:C) significantly reduced the levels of the proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-15 in the intestinal mucosa. In addition, orally administered L. plantarum MPL16 prior nasal stimulation with poly(I:C) or respiratory syncytial virus infection significantly decreased the levels of the biochemical markers of lung tissue damage. In addition, reduced levels of the proinflammatory mediators TNF-α, IL-6, and IL-8 were found in MPL16-treated mice. Improved levels of IFN-β and IFN-γ in the respiratory mucosa were observed in mice treated with L. plantarum MPL16 when compared to control mice. The immunological changes induced by L. plantarum MPL16 were not different from those previously reported for the CRL1505 strain in in vitro and in vivo studies. The results of this work confirm that new immunobiotic strains with the ability of stimulating both local and distal antiviral immune responses can be efficiently selected by evaluating the expression of biomarkers in PIE cells.
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Affiliation(s)
- Leonardo Albarracin
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina.,Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Valeria Garcia-Castillo
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina.,Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepción, Concepción, Chile
| | - Yuki Masumizu
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Yuhki Indo
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Md Aminul Islam
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Yoshihito Suda
- Department of Food, Agriculture and Environment, Miyagi University, Sendai, Japan
| | - Apolinaria Garcia-Cancino
- Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepción, Concepción, Chile
| | - Hisashi Aso
- Cell Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Hideki Takahashi
- Laboratory of Plant Pathology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Plant Immunology Unit, International Education and Research Centre for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Julio Villena
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina.,Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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13
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Albarracin L, Komatsu R, Garcia-Castillo V, Aso H, Iwabuchi N, Xiao JZ, Abe F, Takahashi H, Villena J, Kitazawa H. Deciphering the influence of paraimmunobiotic bifidobacteria on the innate antiviral immune response of bovine intestinal epitheliocytes by transcriptomic analysis. Benef Microbes 2019; 10:199-209. [PMID: 30860402 DOI: 10.3920/bm2018.0024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Previously, we reported that the non-viable immunomodulatory Bifidobacterium infantis MCC12 and Bifidobacterium breve MCC1274 strains (paraimmunobiotic bifidobacteria) were able to increase the protection against rotavirus infection in bovine intestinal epithelial (BIE) cells. In order to gain insight into the influence of paraimmunobiotic bifidobacteria on the innate antiviral immune response of BIE cells, their effect on the transcriptomic response triggered by Toll-like receptor 3 (TLR3) activation was investigated. By using microarray technology and qPCR analysis, we obtained a global overview of the immune genes involved in the innate antiviral immune response in BIE cells. Activation of TLR3 by poly(I:C) in BIE cells significantly increased the expression of interferon (IFN)-α and IFN-β, several interferon-stimulated genes, cytokines, and chemokines. It was also observed that both paraimmunobiotic bifidobacteria differently modulated immune genes expression in poly(I:C)-challenged BIE cells. Most notable changes were found in genes involved in antiviral defence (IFN-β, MX1, OAS1X, MDA5, TLR3, STAT2, STAT3), cytokines (interleukin (IL)-6), and chemokines (CCL2, CXCL2, CXCL6) that were significantly increased in bifidobacteria-treated BIE cells. B. infantis MCC12 and B. breve MCC1274 showed quantitative and qualitative differences in their capacities to modulate the innate antiviral immune response in BIE cells. B. breve MCC1274 was more efficient than the MCC12 strain to improve the production of type I IFNs and antiviral factors, an effect that could be related to its higher ability to protect against rotavirus replication in BIE cells. Interestingly, B. infantis MCC12 showed a remarkable anti-inflammatory effect. The MCC12 strain was more efficient to reduce the expression of inflammatory cytokines and chemokines (IL-16, IL-20, CX3CL1) when compared with B. breve MCC1274. These results provided valuable information for the deeper understanding of the antiviral immune response of intestinal epithelial cells as well as the host-paraimmunobiotic interaction in the bovine host.
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Affiliation(s)
- L Albarracin
- 1 Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Chacabuco 145, Tucuman 4000, Argentina.,2 Immunobiotics Research Group, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,3 Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,9 Scientific Computing Laboratory, Computer Science Department, Faculty of Exact Sciences and Technology, National University of Tucuman, Tucuman, Argentina
| | - R Komatsu
- 3 Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,4 Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan
| | - V Garcia-Castillo
- 2 Immunobiotics Research Group, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,3 Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,5 Laboratory of Bacterial Pathogenicity, Faculty of Biological Sciences, University of Concepcion, Concepcion 4030000, Chile
| | - H Aso
- 4 Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,6 Cell Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan
| | - N Iwabuchi
- 7 Food Ingredients Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - J-Z Xiao
- 8 Next Generation Science Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - F Abe
- 7 Food Ingredients Institute, Morinaga Milk Industry Co. Ltd, Zama, Kanagawa, Japan
| | - H Takahashi
- 10 Laboratory of Plant Pathology, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,11 Plant Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan
| | - J Villena
- 1 Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Chacabuco 145, Tucuman 4000, Argentina.,2 Immunobiotics Research Group, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,3 Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan
| | - H Kitazawa
- 3 Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan.,4 Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai 984-0051, Japan
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14
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Mayassi T, Jabri B. Human intraepithelial lymphocytes. Mucosal Immunol 2018; 11:1281-1289. [PMID: 29674648 PMCID: PMC6178824 DOI: 10.1038/s41385-018-0016-5] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 02/02/2018] [Accepted: 02/03/2018] [Indexed: 02/04/2023]
Abstract
The location of intraepithelial lymphocytes (IEL) between epithelial cells, their effector memory, cytolytic and inflammatory phenotype positions them to kill infected epithelial cells and protect the intestine against pathogens. Human TCRαβ+CD8αβ+ IEL have the dual capacity to recognize modified self via natural killer (NK) receptors (autoreactivity) as well as foreign antigen via the T cell receptor (TCR), which is accomplished in mouse by two cell subsets, the naturally occurring TCRαβ+CD8αα+ and adaptively induced TCRαβ+CD8αβ+ IEL subsets, respectively. The private/oligoclonal nature of the TCR repertoire of both human and mouse IEL suggests local environmental factors dictate the specificity of IEL responses. The line between sensing of foreign antigens and autoreactivity is blurred for IEL in celiac disease, where recognition of stress ligands by induced activating NK receptors in conjunction with inflammatory signals such as IL-15 can result in low-affinity TCR/non-cognate antigen and NK receptor/stress ligand interactions triggering destruction of intestinal epithelial cells.
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Affiliation(s)
- Toufic Mayassi
- Department of Medicine, University of Chicago, Chicago, USA
- Committee on Immunology, University of Chicago, Chicago, USA
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, USA.
- Committee on Immunology, University of Chicago, Chicago, USA.
- Department of Pathology, University of Chicago, Chicago, USA.
- Department of Pediatrics, University of Chicago, Chicago, USA.
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15
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Montalban-Arques A, Chaparro M, Gisbert JP, Bernardo D. The Innate Immune System in the Gastrointestinal Tract: Role of Intraepithelial Lymphocytes and Lamina Propria Innate Lymphoid Cells in Intestinal Inflammation. Inflamm Bowel Dis 2018; 24:1649-1659. [PMID: 29788271 DOI: 10.1093/ibd/izy177] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND The gastrointestinal tract harbors the largest microbiota load in the human body, hence maintaining a delicate balance between immunity against invading pathogens and tolerance toward commensal. Such immune equilibrium, or intestinal homeostasis, is conducted by a tight regulation and cooperation of the different branches of the immune system, including the innate and the adaptive immune system. However, several factors affect this delicate equilibrium, ultimately leading to gastrointestinal disorders including inflammatory bowel disease. Therefore, here we decided to review the currently available information about innate immunity lymphocyte subsets playing a role in intestinal inflammation. RESULTS Intestinal innate lymphocytes are composed of intraepithelial lymphocytes (IELs) and lamina propria innate lymphoid cells (ILCs). While IELs can be divided into natural or induced, ILCs can be classified into type 1, 2, or 3, resembling, respectively, the properties of TH1, TH2, or TH17 adaptive lymphocytes. Noteworthy, the phenotype and function of both IELs and ILCs are disrupted under inflammatory conditions, where they help to exacerbate intestinal immune responses. CONCLUSIONS The modulation of both IELs and ILCs to control intestinal inflammatory responses represents a major challenge, as they provide tight regulation among the epithelium, the microbiota, and the adaptive immune system. An improved understanding of the innate immunity mechanisms involved in gastrointestinal inflammation would therefore aid in the diagnosis and further treatment of gastrointestinal inflammatory disorders.
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Affiliation(s)
- A Montalban-Arques
- Servicio de Aparato Digestivo. Hospital Universitario de La Princesa e Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - M Chaparro
- Servicio de Aparato Digestivo. Hospital Universitario de La Princesa e Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Javier P Gisbert
- Servicio de Aparato Digestivo. Hospital Universitario de La Princesa e Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - D Bernardo
- Servicio de Aparato Digestivo. Hospital Universitario de La Princesa e Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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16
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Villena J, Aso H, Rutten VPMG, Takahashi H, van Eden W, Kitazawa H. Immunobiotics for the Bovine Host: Their Interaction with Intestinal Epithelial Cells and Their Effect on Antiviral Immunity. Front Immunol 2018; 9:326. [PMID: 29599767 PMCID: PMC5863502 DOI: 10.3389/fimmu.2018.00326] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 02/06/2018] [Indexed: 12/11/2022] Open
Abstract
The scientific community has reported several cases of microbes that exhibit elevated rates of antibiotic resistance in different regions of the planet. Due to this emergence of antimicrobial resistant microorganisms, the use of antibiotics as promoters of livestock animals' growth is being banned in most countries around the world. One of the challenges of agricultural immunology therefore is to find alternatives by modulating the immune system of animals in drug-independent safe food production systems. In this regard, in an effort to supplant antibiotics from bovine feeds, several alternatives were proposed including the use of immunomodulatory probiotics (immunobiotics). The purpose of this review is to provide an update of the status of the modulation of intestinal antiviral innate immunity of the bovine host by immunobiotics, and the beneficial impact of immunobiotics on viral infections, focused on intestinal epithelial cells (IECs). The results of our group, which demonstrate the capacity of immunobiotic strains to beneficially modulate Toll-like receptor 3-triggered immune responses in bovine IECs and improve the resistance to viral infections, are highlighted. This review provides comprehensive information on the innate immune response of bovine IECs against virus, which can be further investigated for the development of strategies aimed to improve defenses in the bovine host.
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Affiliation(s)
- Julio Villena
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina.,Immunobiotics Research Group, Tucuman, Argentina.,Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Hisashi Aso
- Cell Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Victor P M G Rutten
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Hideki Takahashi
- Laboratory of Plant Pathology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Plant Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Willem van Eden
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.,Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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17
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Hu MD, Jia L, Edelblum KL. Policing the intestinal epithelial barrier: Innate immune functions of intraepithelial lymphocytes. CURRENT PATHOBIOLOGY REPORTS 2018; 6:35-46. [PMID: 29755893 PMCID: PMC5943048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
PURPOSE OF REVIEW This review will explore the contribution of IELs to mucosal innate immunity and highlight the similarities in IEL functional responses to bacteria, viruses and protozoan parasite invasion. RECENT FINDINGS IELs rapidly respond to microbial invasion by activating host defense responses, including the production of mucus and antimicrobial peptides to prevent microbes from reaching the epithelial surface. During active infection, IELs promote epithelial cytolysis, cytokine and chemokine production to limit pathogen invasion, replication and dissemination. Commensal-induced priming of IEL effector function or continuous surveillance of the epithelium may be important contributing factors to the rapidity of response. SUMMARY Impaired microbial recognition, dysregulated innate immune signaling or microbial dysbiosis may limit the protective function of IELs and increase susceptibility to disease. Further understanding of the mechanisms regulating IEL surveillance and sentinel function may provide insight into the development of more effective targeted therapies designed to reinforce the mucosal barrier.
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Affiliation(s)
- Madeleine D Hu
- Center for Immunity and Inflammation, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Luo Jia
- Center for Immunity and Inflammation, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Karen L Edelblum
- Center for Immunity and Inflammation, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
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Policing the Intestinal Epithelial Barrier: Innate Immune Functions of Intraepithelial Lymphocytes. CURRENT PATHOBIOLOGY REPORTS 2018. [DOI: 10.1007/s40139-018-0157-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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19
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Antonangeli F, Soriani A, Cerboni C, Sciumè G, Santoni A. How Mucosal Epithelia Deal with Stress: Role of NKG2D/NKG2D Ligands during Inflammation. Front Immunol 2017; 8:1583. [PMID: 29209320 PMCID: PMC5701928 DOI: 10.3389/fimmu.2017.01583] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/03/2017] [Indexed: 01/22/2023] Open
Abstract
Mucosal epithelia encounter both physicochemical and biological stress during their life and have evolved several mechanisms to deal with them, including regulation of immune cell functions. Stressed and damaged cells need to be cleared to control local inflammation and trigger tissue healing. Engagement of the activating NKG2D receptor is one of the most direct mechanisms involved in the recognition of stressed cells by the immune system. Indeed, injured cells promptly express NKG2D ligands that in turn mediate the activation of lymphocytes of both innate and adaptive arms of the immune system. This review focuses on different conditions that are able to modulate NKG2D ligand expression on the epithelia. Special attention is given to the mechanisms of immunosurveillance mediated by natural killer cells, which are finely tuned by NKG2D. Different types of stress, including viral and bacterial infections, chronic inflammation, and cigarette smoke exposure, are discussed as paradigmatic conditions for NKG2D ligand modulation, and the implications for tissue homeostasis are discussed.
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Affiliation(s)
- Fabrizio Antonangeli
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Alessandra Soriani
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Cristina Cerboni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Giuseppe Sciumè
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Angela Santoni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy.,Neuromed I.R.C.C.S. - Istituto Neurologico Mediterraneo, Pozzilli, Italy
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Zhao HW, Yue YH, Han H, Chen XL, Lu YG, Zheng JM, Hou HT, Lang XM, He LL, Hu QL, Dun ZQ. Effect of toll-like receptor 3 agonist poly I:C on intestinal mucosa and epithelial barrier function in mouse models of acute colitis. World J Gastroenterol 2017; 23:999-1009. [PMID: 28246473 PMCID: PMC5311109 DOI: 10.3748/wjg.v23.i6.999] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 09/26/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM
To investigate potential effects of poly I:C on mucosal injury and epithelial barrier disruption in dextran sulfate sodium (DSS)-induced acute colitis.
METHODS
Thirty C57BL/6 mice were given either regular drinking water (control group) or 2% (w/v) DSS drinking water (model and poly I:C groups) ad libitum for 7 d. Poly I:C was administrated subcutaneously (20 μg/mouse) 2 h prior to DSS induction in mice of the poly I:C group. Severity of colitis was evaluated by disease activity index, body weight, colon length, histology and myeloperoxidase (MPO) activity, as well as the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin 17 (IL-17) and interferon-γ (IFN-γ). Intestinal permeability was analyzed by the fluorescein isothiocyanate labeled-dextran (FITC-D) method. Ultrastructural features of the colon tissue were observed under electron microscopy. Expressions of tight junction (TJ) proteins, including zo-1, occludin and claudin-1, were measured by immunohistochemistry/immunofluorescence, Western blot and real-time quantitative polymerase chain reaction (RT-qPCR).
RESULTS
DSS caused significant damage to the colon tissue in the model group. Administration of poly I:C dramatically protected against DSS-induced colitis, as demonstrated by less body weight loss, lower disease activity index score, longer colon length, colonic MPO activity, and improved macroscopic and histological scores. It also ameliorated DSS-induced ultrastructural changes of the colon epithelium, as observed under scanning electron microscopy, as well as FITC-D permeability. The mRNA and protein expressions of TJ protein, zo-1, occludin and claudin-1 were also found to be significantly enhanced in the poly I:C group, as determined by immunohistochemistry/immunofluorescence, Western blot and RT-qPCR. By contrast, poly I:C pretreatment markedly reversed the DSS-induced up-regulated expressions of the inflammatory cytokines TNF-α, IL-17 and IFN-γ.
CONCLUSION
Our study suggested that poly I:C may protect against DSS-induced colitis through maintaining integrity of the epithelial barrier and regulating innate immune responses, which may shed light on the therapeutic potential of poly I:C in human colitis.
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Albarracin L, Kobayashi H, Iida H, Sato N, Nochi T, Aso H, Salva S, Alvarez S, Kitazawa H, Villena J. Transcriptomic Analysis of the Innate Antiviral Immune Response in Porcine Intestinal Epithelial Cells: Influence of Immunobiotic Lactobacilli. Front Immunol 2017; 8:57. [PMID: 28210256 PMCID: PMC5288346 DOI: 10.3389/fimmu.2017.00057] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 01/16/2017] [Indexed: 01/14/2023] Open
Abstract
Lactobacillus rhamnosus CRL1505 and Lactobacillus plantarum CRL1506 are immunobiotic strains able to increase protection against viral intestinal infections as demonstrated in animal models and humans. To gain insight into the host–immunobiotic interaction, the transcriptomic response of porcine intestinal epithelial (PIE) cells to the challenge with viral molecular associated pattern poly(I:C) and the changes in the transcriptomic profile induced by the immunobiotics strains CRL1505 and CRL1506 were investigated in this work. By using microarray technology and reverse transcription PCR, we obtained a global overview of the immune genes involved in the innate antiviral immune response in PIE cells. Stimulation of PIE cells with poly(I:C) significantly increased the expression of IFN-α and IFN-β, several interferon-stimulated genes, cytokines, chemokines, adhesion molecules, and genes involved in prostaglandin biosynthesis. It was also determined that lactobacilli differently modulated immune gene expression in poly(I:C)-challenged PIE cells. Most notable changes were found in antiviral factors (IFN-α, IFN-β, NPLR3, OAS1, OASL, MX2, and RNASEL) and cytokines/chemokines (IL-1β, IL-6, CCL4, CCL5, and CXCL10) that were significantly increased in lactobacilli-treated PIE cells. Immunobiotics reduced the expression of IL-15 and RAE1 genes that mediate poly(I:C) inflammatory damage. In addition, lactobacilli treatments increased the expression PLA2G4A, PTGES, and PTGS2 that are involved in prostaglandin E2 biosynthesis. L. rhamnosus CRL1505 and L. plantarum CRL1506 showed quantitative and qualitative differences in their capacities to modulate the innate antiviral immune response in PIE cells, which would explain the higher capacity of the CRL1505 strain when compared to CRL1506 to protect against viral infection and inflammatory damage in vivo. These results provided valuable information for the deeper understanding of the host–immunobiotic interaction and their effect on antiviral immunity. The comprehensive transcriptomic analyses successfully identified a group of genes (IFN-β, RIG1, RNASEL, MX2, A20, IL27, CXCL5, CCL4, PTGES, and PTGER4), which can be used as prospective biomarkers for the screening of new antiviral immunobiotics in PIE cells and for the development of novel functional food and feeds, which may help to prevent viral infections.
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Affiliation(s)
- Leonardo Albarracin
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina; Immunobiotics Research Group, Tucuman, Argentina; Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Hisakazu Kobayashi
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Hikaru Iida
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Nana Sato
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Tomonori Nochi
- Cell Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Infection Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Hisashi Aso
- Cell Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Infection Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Susana Salva
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina; Immunobiotics Research Group, Tucuman, Argentina
| | - Susana Alvarez
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina; Immunobiotics Research Group, Tucuman, Argentina
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Livestock Immunology Unit, International Education and Research Center for Food Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Julio Villena
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina; Immunobiotics Research Group, Tucuman, Argentina; Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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Villena J, Vizoso-Pinto MG, Kitazawa H. Intestinal Innate Antiviral Immunity and Immunobiotics: Beneficial Effects against Rotavirus Infection. Front Immunol 2016; 7:563. [PMID: 27994593 PMCID: PMC5136547 DOI: 10.3389/fimmu.2016.00563] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 11/22/2016] [Indexed: 12/13/2022] Open
Abstract
The mucosal tissues of the gastrointestinal tract are the main portal entry of pathogens such as rotavirus (RV), which is a leading cause of death due to diarrhea among young children across the globe and a major cause of severe acute intestinal infection in livestock animals. The interactions between intestinal epithelial cells (IECs) and immune cells with RVs have been studied for several years, and now, it is known that the innate immune responses triggered by this virus can have both beneficial and detrimental effects for the host. It was demonstrated that natural RV infection in infants and experimental challenges in mice result in the intestinal activation of pattern recognition receptors (PRRs) such as toll-like receptor 3 (TLR3) and striking secretion of proinflammatory mediators that can lead to increased local tissue damage and immunopathology. Therefore, modulating desregulated intestinal immune responses triggered by PRRs activation are a significant promise for reducing the burden of RV diseases. The ability of immunoregulatory probiotic microorganisms (immunobiotics) to protect against intestinal infections, such as those caused by RVs, is among the oldest effects studied for these important group of beneficial microbes. In this review, we provide an update of the current status on the modulation of intestinal antiviral innate immunity by immunobiotics and their beneficial impact on RV infection. In addition, we describe the research of our group that demonstrated the capacity of immunobiotic strains to beneficially modulated TLR3-triggered immune response in IECs, reduce the disruption of intestinal homeostasis caused by intraepithelial lymphocytes, and improve the resistance to RV infections.
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Affiliation(s)
- Julio Villena
- Immunobiotics Research Group, Tucuman, Argentina; Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina; Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Maria Guadalupe Vizoso-Pinto
- Immunobiotics Research Group, Tucuman, Argentina; Faculty of Medicine, INSIBIO (UNT-CONICET), National University of Tucuman, Tucuman, Argentina
| | - Haruki Kitazawa
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA-CONICET), Tucuman, Argentina; Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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23
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Immunobiotic Lactobacillus strains reduce small intestinal injury induced by intraepithelial lymphocytes after Toll-like receptor 3 activation. Inflamm Res 2016; 65:771-83. [PMID: 27279272 DOI: 10.1007/s00011-016-0957-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 05/24/2016] [Accepted: 06/01/2016] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Intestinal intraepithelial lymphocytes (IELs) play critical roles in disrupting epithelial homeostasis after Toll-like receptor (TLR)-3 activation with genomic rotavirus dsRNA or the synthetic dsRNA analog poly(I:C). The capacity of immunobiotic Lactobacillus rhamnosus CRL1505 (Lr1505) or Lactobacillus plantarum CRL1506 (Lp1506) to beneficially modulate IELs response after TLR3 activation was investigated in vivo using a mice model. RESULTS Intraperitoneal administration of poly(I:C) induced inflammatory-mediated intestinal tissue damage through the increase of inflammatory cells (CD3(+)NK1.1(+), CD3(+)CD8αα(+), CD8αα(+)NKG2D(+)) and pro-inflammatory mediators (TNF-α, IL-1β, IFN-γ, IL-15, RAE1, IL-8). Increased expression of intestinal TLR3, MDA5, and RIG-I was also observed after poly(I:C) challenge. Treatment with Lr1505 or Lp1506 prior to TLR3 activation significantly reduced the levels of TNF-α, IL-15, RAE1, and increased serum and intestinal IL-10. Moreover, CD3(+)NK1.1(+), CD3(+)CD8αα(+), and CD8αα(+)NKG2D(+) cells were lower in lactobacilli-treated mice when compared to controls. The immunomodulatory capacities of lactobacilli allowed a significant reduction of intestinal tissue damage. CONCLUSIONS This work demonstrates the reduction of TLR3-mediated intestinal tissue injury by immunobiotic lactobacilli through the modulation of intraepithelial lymphocytes response. It is a step forward in the understanding of the cellular mechanisms involved in the antiviral capabilities of immunobiotic strains.
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24
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Ruiz J, Kanagavelu S, Flores C, Romero L, Riveron R, Shih DQ, Fukata M. Systemic Activation of TLR3-Dependent TRIF Signaling Confers Host Defense against Gram-Negative Bacteria in the Intestine. Front Cell Infect Microbiol 2016; 5:105. [PMID: 26793623 PMCID: PMC4710052 DOI: 10.3389/fcimb.2015.00105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 12/24/2015] [Indexed: 12/11/2022] Open
Abstract
Recognition of Gram-negative bacteria by toll-like receptor (TLR)4 induces MyD88 and TRIF mediated responses. We have shown that TRIF-dependent responses play an important role in intestinal defense against Gram-negative enteropathogens. In the current study, we examined underlying mechanisms of how systemic TRIF activation enhances intestinal immune defense against Gram-negative bacteria. First we confirmed that the protective effect of poly I:C against enteric infection of mice with Yersinia enterocolitica was dependent on TLR3-mediated TRIF signaling by using TLR3-deficient mice. This protection was unique in TRIF-dependent TLR signaling because systemic stimulation of mice with agonists for TLR2 (Pam3CSK4) or TLR5 (flagellin) did not reduce mortality on Y. enterocolitica infection. Systemic administration of poly I:C mobilized CD11c+, F4/80+, and Gr−1hi cells from lamina propria and activated NK cells in the mesenteric lymph nodes (MLN) within 24 h. This innate immune cell rearrangement was type I IFN dependent and mediated through upregulation of TLR4 followed by CCR7 expression in these innate immune cells found in the intestinal mucosa. Poly I:C induced IFN-γ expression by NK cells in the MLN, which was mediated through type I IFNs and IL-12p40 from antigen presenting cells and consequent activation of STAT1 and STAT4 in NK cells. This formation of innate immunity significantly contributed to the elimination of bacteria in the MLN. Our results demonstrated an innate immune network in the intestine that can be established by systemic stimulation of TRIF, which provides a strong host defense against Gram-negative pathogens. The mechanism underlying TRIF-mediated protective immunity may be useful to develop novel therapies for enteric bacterial infection.
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Affiliation(s)
- Jose Ruiz
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine Miami, FL, USA
| | - Saravana Kanagavelu
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of MedicineMiami, FL, USA; Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research InstituteLos Angeles, CA, USA
| | - Claudia Flores
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute Los Angeles, CA, USA
| | - Laura Romero
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine Miami, FL, USA
| | - Reldy Riveron
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine Miami, FL, USA
| | - David Q Shih
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research InstituteLos Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, USA
| | - Masayuki Fukata
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of MedicineMiami, FL, USA; Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research InstituteLos Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, USA; Department of Cell Biology, University of Miami Miller School of MedicineMiami, FL, USA; Department of Biomedical Science, Cedars-Sinai Medical CenterLos Angeles, CA, USA
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25
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Jabri B, Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol 2015; 15:771-83. [PMID: 26567920 PMCID: PMC5079184 DOI: 10.1038/nri3919] [Citation(s) in RCA: 236] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In this Opinion article, we discuss the function of tissues as a crucial checkpoint for the regulation of effector T cell responses, and the notion that interleukin-15 (IL-15) functions as a danger molecule that communicates to the immune system that the tissue is under attack and poises it to mediate tissue destruction. More specifically, we propose that expression of IL-15 in tissues promotes T helper 1 cell-mediated immunity and provides co-stimulatory signals to effector cytotoxic T cells to exert their effector functions and drive tissue destruction. Therefore, we think that IL-15 contributes to tissue protection by promoting the elimination of infected cells but that when its expression is chronically dysregulated, it can promote the development of complex T cell-mediated disorders associated with tissue destruction, such as coeliac disease and type 1 diabetes.
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Affiliation(s)
- Bana Jabri
- Departments of Medicine, Pathology and Pediatrics, University of Chicago, Knapp Center for Biomedical Discovery (KCBD), Chicago, Illinois 60637, USA
| | - Valérie Abadie
- Department of Microbiology, Infectious Diseases, and Immunology, University of Montreal, and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada
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26
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Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. ACTA ACUST UNITED AC 2014; 211:2397-410. [PMID: 25366965 PMCID: PMC4235643 DOI: 10.1084/jem.20140625] [Citation(s) in RCA: 358] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Wang et al. examine how influenza A virus causes GI symptoms. Intranasal infection in mice causes intestinal pathology via virally activated CD4 T cells in the lung up-regulating CCR9 and migrating to the intestine where they secrete IFN-γ that alters homeostasis of the microbiota. Subsequent induction of IL-15 aids differentiation into pathogenic Th17 cells in the gut. Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9+CD4+ T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease.
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Affiliation(s)
- Jian Wang
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Fengqi Li
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Haiming Wei
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Zhe-Xiong Lian
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Rui Sun
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Zhigang Tian
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
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27
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Purine-metabolizing ectoenzymes control IL-8 production in human colon HT-29 cells. Mediators Inflamm 2014; 2014:879895. [PMID: 25242873 PMCID: PMC4158428 DOI: 10.1155/2014/879895] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 07/03/2014] [Indexed: 12/20/2022] Open
Abstract
Interleukin-8 (IL-8) plays key roles in both chronic inflammatory diseases and tumor modulation. We previously observed that IL-8 secretion and function can be modulated by nucleotide (P2) receptors. Here we investigated whether IL-8 release by intestinal epithelial HT-29 cells, a cancer cell line, is modulated by extracellular nucleotide metabolism. We first identified that HT-29 cells regulated adenosine and adenine nucleotide concentration at their surface by the expression of the ectoenzymes NTPDase2, ecto-5′-nucleotidase, and adenylate kinase. The expression of the ectoenzymes was evaluated by RT-PCR, qPCR, and immunoblotting, and their activity was analyzed by RP-HPLC of the products and by detection of Pi produced from the hydrolysis of ATP, ADP, and AMP. In response to poly (I:C), with or without ATP and/or ADP, HT-29 cells released IL-8 and this secretion was modulated by the presence of NTPDase2 and adenylate kinase. Taken together, these results demonstrate the presence of 3 ectoenzymes at the surface of HT-29 cells that control nucleotide levels and adenosine production (NTPDase2, ecto-5′-nucleotidase and adenylate kinase) and that P2 receptor-mediated signaling controls IL-8 release in HT-29 cells which is modulated by the presence of NTPDase2 and adenylate kinase.
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28
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Lacroix-Lamandé S, Guesdon W, Drouet F, Potiron L, Lantier L, Laurent F. The gut flora is required for the control of intestinal infection by poly(I:C) administration in neonates. Gut Microbes 2014; 5:533-40. [PMID: 24918602 DOI: 10.4161/gmic.29154] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
We found that immunostimulation of the intestinal immune system of neonatal mice by poly(I:C) injection decreased intestinal infection by the parasite Cryptosporidium parvum. We showed that the presence of dendritic cells and the cooperation of mutually dependent cytokines, such as IL-12p40, and type I and type II IFNs, were involved in the mechanism of protection induced by poly(I:C). This protection is dependent not only on TLR3-TRIF signaling, but also on the activation of the TLR5-MyD88 pathway by gut microbiota. These results raise the possibility that flagellated intestinal commensal bacteria may, in the presence of natural or synthetic agonists of TLR3, provide synergy between the TRIF and MyD88 signaling pathways, thereby favoring the development of mucosal defenses. In this addendum, we summarize these recent findings and discuss their implications for neonatal infections and immunomodulatory strategies.
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Affiliation(s)
- Sonia Lacroix-Lamandé
- INRA Val de Loire; UMR 1282 Infectiologie et Santé Publique, F-37380; Nouzilly, France; Université François Rabelais; UMR 1282 Infectiologie et Santé Publique, F-37000 ; Tours, France
| | - William Guesdon
- INRA Val de Loire; UMR 1282 Infectiologie et Santé Publique, F-37380; Nouzilly, France; Université François Rabelais; UMR 1282 Infectiologie et Santé Publique, F-37000 ; Tours, France
| | - Françoise Drouet
- INRA Val de Loire; UMR 1282 Infectiologie et Santé Publique, F-37380; Nouzilly, France; Université François Rabelais; UMR 1282 Infectiologie et Santé Publique, F-37000 ; Tours, France
| | - Laurent Potiron
- INRA Val de Loire; UMR 1282 Infectiologie et Santé Publique, F-37380; Nouzilly, France; Université François Rabelais; UMR 1282 Infectiologie et Santé Publique, F-37000 ; Tours, France
| | - Louis Lantier
- INRA Val de Loire; UMR 1282 Infectiologie et Santé Publique, F-37380; Nouzilly, France; Université François Rabelais; UMR 1282 Infectiologie et Santé Publique, F-37000 ; Tours, France
| | - Fabrice Laurent
- INRA Val de Loire; UMR 1282 Infectiologie et Santé Publique, F-37380; Nouzilly, France; Université François Rabelais; UMR 1282 Infectiologie et Santé Publique, F-37000 ; Tours, France
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Araya RE, Jury J, Bondar C, Verdu EF, Chirdo FG. Intraluminal administration of poly I:C causes an enteropathy that is exacerbated by administration of oral dietary antigen. PLoS One 2014; 9:e99236. [PMID: 24915573 PMCID: PMC4051664 DOI: 10.1371/journal.pone.0099236] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 05/13/2014] [Indexed: 01/13/2023] Open
Abstract
Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen.
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Affiliation(s)
- Romina E Araya
- Laboratorio de Investigación en el Sistema Inmune- LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Jennifer Jury
- Division of Gastroenterology, Farncombe Family Digestive Health Institute, McMaster University, Hamilton, Canada
| | - Constanza Bondar
- Laboratorio de Investigación en el Sistema Inmune- LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Elena F Verdu
- Division of Gastroenterology, Farncombe Family Digestive Health Institute, McMaster University, Hamilton, Canada
| | - Fernando G Chirdo
- Laboratorio de Investigación en el Sistema Inmune- LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
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Marietta EV, Rubio-Tapia A, Murray JA. Using Animal Models of Celiac Disease to Understand the Role of MHC II. CLINICAL GASTROENTEROLOGY 2014. [DOI: 10.1007/978-1-4614-8560-5_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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31
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van Leeuwen MA, Lindenbergh-Kortleve DJ, Raatgeep HC, de Ruiter LF, de Krijger RR, Groeneweg M, Escher JC, Samsom JN. Increased production of interleukin-21, but not interleukin-17A, in the small intestine characterizes pediatric celiac disease. Mucosal Immunol 2013; 6:1202-13. [PMID: 23571506 DOI: 10.1038/mi.2013.19] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 03/01/2013] [Indexed: 02/04/2023]
Abstract
Celiac disease (CD) is caused by inflammatory CD4(+) T-cell responses to dietary gluten. It is unclear whether interleukin (IL)-21 and IL-17A contribute to CD onset and lesion severity; therefore, we investigated IL-21 and IL-17A expression in biopsies from pediatric CD patients with different histopathological scores. High numbers of IL-21-producing cells were observed in pediatric CD lesions, even Marsh 1-2 lesions, whereas increased numbers of IL-17 secreting cells were not observed. Intraepithelial lymphocytes, CD4(+) T cells and also neutrophils secreted IL-21. Flow cytometry of lamina propria cells revealed a large population of IL-21- and interferon-γ (IFN-γ)-secreting CD3(+) T cells that did not secrete IL-17A. Adult CD patient biopsies also contained high numbers of IL-21-positive cells; however, enhanced numbers of IL-17-positive cells were observed in a small subgroup of patients with severe lesions. As duodenal tissue damage increases contact with microbe-associated molecular patterns, we hypothesized that microbial sensing by Toll-like receptors (TLRs) modulates T cell-derived cytokine secretion. Costimulation with TLR3 ligands during polyclonal T-cell activation significantly increased IL-21 secretion, whereas TLR2 ligands selectively enhanced IL-17A. These results demonstrate that an IL-17A-independent increase in IL-21 production by CD4(+) T cells is characteristic of pediatric CD. We hypothesize that incidental IL-17 secretion is caused by tissue damage rather than gluten-specific responses.
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Affiliation(s)
- M A van Leeuwen
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
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Wortham BW, Eppert BL, Flury JL, Morgado Garcia S, Borchers MT. TLR and NKG2D signaling pathways mediate CS-induced pulmonary pathologies. PLoS One 2013; 8:e78735. [PMID: 24130907 PMCID: PMC3793989 DOI: 10.1371/journal.pone.0078735] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 09/23/2013] [Indexed: 11/19/2022] Open
Abstract
Long-term exposure to cigarette smoke (CS) can have deleterious effects on lung epithelial cells including cell death and the initiation of inflammatory responses. CS-induced cell injury can elaborate cell surface signals and cellular byproducts that stimulate immune system surveillance. Our previous work has shown that the expression of ligands for the cytotoxic lymphocyte activating receptor NKG2D is enhanced in patients with COPD and that the induction of these ligands in a mouse model can replicate COPD pathologies. Here, we extend these findings to demonstrate a role for the NKG2D receptor in CS-induced pathophysiology and provide evidence linking nucleic acid-sensing endosomal toll-like receptor (TLR) signaling to COPD pathology through NKG2D activation. Specifically, we show that mice deficient in NKG2D exhibit attenuated pulmonary inflammation and airspace enlargement in a model of CS-induced emphysema. Additionally, we show that CS exposure induces the release of free nucleic acids in the bronchoalveolar lavage and that direct exposure of mouse lung epithelial cells to cigarette smoke extract similarly induces functional nucleic acids as assessed by TLR3, 7, and 9 reporter cell lines. We demonstrate that exposure of mouse lung epithelial cells to TLR ligands stimulates the surface expression of RAET1, a ligand for NKG2D, and that mice deficient in TLR3/7/9 receptor signaling do not exhibit CS-induced NK cell hyperresponsiveness and airspace enlargement. The findings indicate that CS-induced airway injury stimulates TLR signaling by endogenous nucleic acids leading to elevated NKG2D ligand expression. Activation of these pathways plays a major role in the altered NK cell function, pulmonary inflammation and remodeling related to long-term CS exposure.
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Affiliation(s)
- Brian W. Wortham
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Bryan L. Eppert
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Jennifer L. Flury
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Sara Morgado Garcia
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Michael T. Borchers
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
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Jiang W, Wang X, Zeng B, Liu L, Tardivel A, Wei H, Han J, MacDonald HR, Tschopp J, Tian Z, Zhou R. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. ACTA ACUST UNITED AC 2013; 210:2465-76. [PMID: 24062413 PMCID: PMC3804938 DOI: 10.1084/jem.20122490] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
NOD2 signaling maintains intestinal intraepithelial lymphocytes via recognition of gut microbiota and IL-15 production. NOD2 functions as an intracellular sensor for microbial pathogen and plays an important role in epithelial defense. The loss-of-function mutation of NOD2 is strongly associated with human Crohn’s disease (CD). However, the mechanisms of how NOD2 maintains the intestinal homeostasis and regulates the susceptibility of CD are still unclear. Here we found that the numbers of intestinal intraepithelial lymphocytes (IELs) were reduced significantly in Nod2−/− mice and the residual IELs displayed reduced proliferation and increased apoptosis. Further study showed that NOD2 signaling maintained IELs via recognition of gut microbiota and IL-15 production. Notably, recovery of IELs by adoptive transfer could reduce the susceptibility of Nod2−/− mice to the 2,4,6-trinitrobenzene sulfonic acid (TNBS)–induced colitis. Our results demonstrate that recognition of gut microbiota by NOD2 is important to maintain the homeostasis of IELs and provide a clue that may link NOD2 variation to the impaired innate immunity and higher susceptibility in CD.
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Affiliation(s)
- Wei Jiang
- the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China
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Guerra N, Pestal K, Juarez T, Beck J, Tkach K, Wang L, Raulet DH. A selective role of NKG2D in inflammatory and autoimmune diseases. Clin Immunol 2013; 149:432-9. [PMID: 24211717 DOI: 10.1016/j.clim.2013.09.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 09/05/2013] [Accepted: 09/06/2013] [Indexed: 02/04/2023]
Abstract
The NKG2D activating receptor has been implicated in numerous autoimmune diseases. We tested the role of NKG2D in models of autoimmunity and inflammation using NKG2D knockout mice and antibody blockade experiments. The severity of experimental autoimmune encephalitis (EAE) was decreased in NKG2D-deficient mice when the disease was induced with a limiting antigen dose, but unchanged with an optimal antigen dose. Surprisingly, however, NKG2D deficiency had no detectable effect in several other models, including two models of type 1 diabetes, and a model of intestinal inflammation induced by poly(I:C). NKG2D antibody blockade in normal mice also failed to inhibit disease in the NOD diabetes model or the intestinal inflammation model. Published evidence using NKG2D knockout mice demonstrated a role for NKG2D in mouse models of atherosclerosis and liver inflammation, as well as in chronic obstructive pulmonary disease. Therefore, our results suggest that NKG2D plays selective roles in inflammatory diseases.
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Affiliation(s)
- Nadia Guerra
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA.,Department of Life Science, Imperial College London, Imperial College Road, SW7 2AZ, London
| | - Kathleen Pestal
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA
| | - Tiffany Juarez
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA
| | - Jennifer Beck
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA
| | - Karen Tkach
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA
| | - Lin Wang
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA
| | - David H Raulet
- Department of Molecular and Cell Biology, and Cancer Research Laboratory, 489 Life Sciences, Addition, University of California at Berkeley, Berkeley, CA 94720, USA
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35
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Thaxton JE, Nevers T, Lippe EO, Blois SM, Saito S, Sharma S. NKG2D blockade inhibits poly(I:C)-triggered fetal loss in wild type but not in IL-10-/- mice. THE JOURNAL OF IMMUNOLOGY 2013; 190:3639-47. [PMID: 23455498 DOI: 10.4049/jimmunol.1203488] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Infection and inflammation can disturb immune tolerance at the maternal-fetal interface, resulting in adverse pregnancy outcomes. However, the underlying mechanisms for detrimental immune responses remain ill defined. In this study, we provide evidence for immune programming of fetal loss in response to polyinosinic:polycytidylic acid (polyI:C), a viral mimic and an inducer of inflammatory milieu. IL-10 and uterine NK (uNK) cells expressing the activating receptor NKG2D play a critical role in poly(I:C)-induced fetal demise. In wild type (WT) mice, poly(I:C) treatment induced expansion of NKG2D(+) uNK cells and expression of Rae-1 (an NKG2D ligand) on uterine macrophages and led to fetal resorption. In IL-10(-/-) mice, NKG2D(-) T cells instead became the source of fetal resorption during the same gestation period. Interestingly, both uterine NK and T cells produced TNF-α as the key cytotoxic factor contributing to fetal loss. Treatment of WT mice with poly(I:C) resulted in excessive trophoblast migration into the decidua and increased TUNEL-positive signal. IL-10(-/-) mice supplemented with recombinant IL-10 induced fetal loss through NKG2D(+) uNK cells, similar to the response in WT mice. Blockade of NKG2D in poly(I:C)-treated WT mice led to normal pregnancy outcome. Thus, we demonstrate that pregnancy-disrupting inflammatory events mimicked by poly(I:C) are regulated by IL-10 and depend on the effector function of uterine NKG2D(+) NK cells in WT mice and NKG2D(-) T cells in IL-10 null mice.
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Affiliation(s)
- Jessica E Thaxton
- Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA
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36
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Hansen CHF, Holm TL, Krych Ł, Andresen L, Nielsen DS, Rune I, Hansen AK, Skov S. Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells. Eur J Immunol 2012; 43:447-57. [PMID: 23136011 DOI: 10.1002/eji.201242462] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 09/27/2012] [Accepted: 11/02/2012] [Indexed: 12/14/2022]
Abstract
Intestinal epithelial cells (IECs) are one of a few cell types in the body with constitutive surface expression of natural killer group 2 member D (NKG2D) ligands, although the magnitude of ligand expression by IECs varies. Here, we investigated whether the gut microbiota regulates the NKG2D ligand expression on small IECs. Germ-free and ampicillin-treated mice were shown to have a significant increase in NKG2D ligand expression. Interestingly, vancomycin treatment, which propagated the bacterium Akkermansia muciniphila and reduced the level of IFN-γ and IL-15 in the intestine, decreased the NKG2D ligand expression on IECs. In addition, a similar increase in A. muciniphila and a decreased NKG2D ligand expression was seen after feeding with dietary xylooligosaccharides. A pronounced increase in NKG2D ligand expression was furthermore observed in IL-10-deficient mice. In summary, our results suggest that the constitutive levels of NKG2D ligand expression on IECs are regulated by microbial signaling in the gut and further disfavor the intuitive notion that IEC NKG2D ligand expression is caused by low-grade immune reaction against commensal bacteria. It is more likely that constitutively high IEC NKG2D ligand expression is kept in check by an intestinal regulatory immune milieu induced by members of the gut microbiota, for example A. muciniphila.
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Affiliation(s)
- Camilla H F Hansen
- Section of Biomedicine, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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37
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McAllister CS, Lakhdari O, Pineton de Chambrun G, Gareau MG, Broquet A, Lee GH, Shenouda S, Eckmann L, Kagnoff MF. TLR3, TRIF, and caspase 8 determine double-stranded RNA-induced epithelial cell death and survival in vivo. THE JOURNAL OF IMMUNOLOGY 2012; 190:418-27. [PMID: 23209324 DOI: 10.4049/jimmunol.1202756] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
TLR3 signaling is activated by dsRNA, a virus-associated molecular pattern. Injection of dsRNA into mice induced a rapid, dramatic, and reversible remodeling of the small intestinal mucosa with significant villus shortening. Villus shortening was preceded by increased caspase 3 and 8 activation and apoptosis of intestinal epithelial cells (IECs) located in the mid to upper villus with ensuing luminal fluid accumulation and diarrhea because of an increased secretory state. Mice lacking TLR3 or the adaptor molelcule TRIF mice were completely protected from dsRNA-induced IEC apoptosis, villus shortening, and diarrhea. dsRNA-induced apoptosis was independent of TNF signaling. Notably, NF-κB signaling through IκB kinase β protected crypt IECs but did not protect villus IECs from dsRNA-induced or TNF-induced apoptosis. dsRNA did not induce early caspase 3 activation with subsequent villus shortening in mice lacking caspase 8 in IECs but instead caused villus destruction with a loss of small intestinal surface epithelium and death. Consistent with direct activation of the TLR3-TRIF-caspase 8 signaling pathway by dsRNA in IECs, dsRNA-induced signaling of apoptosis was independent of non-TLR3 dsRNA signaling pathways, IL-15, TNF, IL-1, IL-6, IFN regulatory factor 3, type I IFN receptor, adaptive immunity, as well as dendritic cells, NK cells, and other hematopoietic cells. We conclude that dsRNA activation of the TLR3-TRIF-caspase 8 signaling pathway in IECs has a significant impact on the structure and function of the small intestinal mucosa and suggest signaling through this pathway has a host protective role during infection with viral pathogens.
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Schulthess J, Meresse B, Ramiro-Puig E, Montcuquet N, Darche S, Bègue B, Ruemmele F, Combadière C, Di Santo JP, Buzoni-Gatel D, Cerf-Bensussan N. Interleukin-15-dependent NKp46+ innate lymphoid cells control intestinal inflammation by recruiting inflammatory monocytes. Immunity 2012; 37:108-21. [PMID: 22705105 DOI: 10.1016/j.immuni.2012.05.013] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Revised: 03/22/2012] [Accepted: 05/03/2012] [Indexed: 12/26/2022]
Abstract
With the goal in mind to define how interleukin-15 (IL-15) contributes to acute intestinal inflammation, we have used a mouse model of ileitis induced by oral infection with Toxoplasma gondii. We observed that a crosstalk between IL-15 and interleukin-18 (IL-18) promoted intestinal recruitment of inflammatory monocytes, where these cells participated in parasite control but also in tissue damage. A stromal source of IL-15 controlled the development of lamina propria NKp46(+)NK1.1(+) cells, whereas IL-18 produced during T. gondii infection stimulated their production of the chemokine CCL3. In turn, CCL3 attracted inflammatory monocytes via their chemokine receptor CCR1, which was indispensable for their recruitment into the inflamed gut. Collectively, these results identify the IL-15-dependent subset of intestinal NKp46(+) cells as an important source of CCL3, which can amplify intestinal inflammation via the recruitment of CCR1(+) inflammatory monocytes. Preliminary evidence suggests that this pathway might operate in Crohn's disease.
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Affiliation(s)
- Julie Schulthess
- INSERM, U989, 75015 Paris, France; Université Paris Descartes, Paris Sorbonne Cité, Institut Imagine, France
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Jin B, Sun T, Yu XH, Yang YX, Yeo AET. The effects of TLR activation on T-cell development and differentiation. Clin Dev Immunol 2012; 2012:836485. [PMID: 22737174 PMCID: PMC3376488 DOI: 10.1155/2012/836485] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Accepted: 01/26/2012] [Indexed: 02/07/2023]
Abstract
Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.
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Affiliation(s)
- Bo Jin
- Department of Gastroenterology, The 309th Hospital of The People's Liberation Army, Beijing 100091, China
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
| | - Tao Sun
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
| | - Xiao-Hong Yu
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
| | - Ying-Xiang Yang
- Department of Infectious Diseases, Naval General Hospital, Beijing 100048, China
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Abadie V, Discepolo V, Jabri B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin Immunopathol 2012; 34:551-66. [PMID: 22660791 DOI: 10.1007/s00281-012-0316-x] [Citation(s) in RCA: 133] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 04/16/2012] [Indexed: 12/21/2022]
Abstract
Celiac disease is a T cell-mediated immune disorder induced by dietary gluten that is characterized by the development of an inflammatory anti-gluten CD4 T cell response, anti-gluten antibodies, and autoantibodies against tissue transglutaminase 2 and the activation of intraepithelial lymphocytes (IELs) leading to the destruction of the intestinal epithelium. Intraepithelial lymphocytes represent a heterogeneous population of T cells composed mainly of cytotoxic CD8 T cells residing within the epithelial layer, whose main role is to maintain the integrity of the epithelium by eliminating infected cells and promoting epithelial repair. Dysregulated activation of IELs is a hallmark of CD and is critically involved in epithelial cell destruction and the subsequent development of villous atrophy. In this review, we compare and contrast the phenotype and function of human and mouse small intestinal IELs under physiological conditions. Furthermore, we discuss how conditions of epithelial distress associated with overexpression of IL-15 and non-classical MHC class I molecules induce cytotoxic IELs to become licensed killer cells that upregulate activating NKG2D and CD94/NKG2C natural killer receptors, acquiring lymphokine killer activity. Pathways leading to dysregulated IEL activation could eventually be targeted to prevent villous atrophy and treat patients who respond poorly to gluten-free diet.
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Affiliation(s)
- Valérie Abadie
- Sainte-Justine Hospital Research Centre, Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1C5, Canada.
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Abstract
Transglutaminase 2 (TG2) is an allosterically regulated enzyme with transamidating, deamidating and cell signaling activities. It is thought to catalyze sequence-specific deamidation of dietary gluten peptides in the small intestines of celiac disease patients. Because this modification has profound consequences for disease pathogenesis, there is considerable interest in the design of small molecule TG2 inhibitors. Although many classes of TG2 inhibitors have been reported, thus far an animal model for screening them to identify promising celiac drug candidates has remained elusive. Using intraperitoneal administration of the toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly(I∶C)), we induced rapid TG2 activation in the mouse small intestine. Dose dependence was observed in the activation of TG2 as well as the associated villous atrophy, gross clinical response, and rise in serum concentration of the IL-15/IL-15R complex. TG2 activity was most pronounced in the upper small intestine. No evidence of TG2 activation was observed in the lung mucosa, nor were TLR7/8 ligands able to elicit an analogous response. Introduction of ERW1041E, a small molecule TG2 inhibitor, in this mouse model resulted in TG2 inhibition in the small intestine. TG2 inhibition had no effect on villous atrophy, suggesting that activation of this enzyme is a consequence, rather than a cause, of poly(I∶C) induced enteropathy. Consistent with this finding, administration of poly(I∶C) to TG2 knockout mice also induced villous atrophy. Our findings pave the way for pharmacological evaluation of small molecule TG2 inhibitors as drug candidates for celiac disease.
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Radulovic K, Manta C, Rossini V, Holzmann K, Kestler HA, Wegenka UM, Nakayama T, Niess JH. CD69 regulates type I IFN-induced tolerogenic signals to mucosal CD4 T cells that attenuate their colitogenic potential. THE JOURNAL OF IMMUNOLOGY 2012; 188:2001-13. [PMID: 22250092 DOI: 10.4049/jimmunol.1100765] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
CD69 is highly expressed by lymphocytes at mucosal surfaces. We aimed to investigate the role of CD69 in mucosal immune responses. The expression of CD69 by CD4 T cells isolated from the spleen, mesenteric lymph nodes, small intestinal lamina propria, and colonic lamina propria was determined in specific pathogen-free B6 and TCR transgenic animals, as well as in germ-free B6 mice. Transfer colitis was induced by transplanting RAG(-/-) mice with B6 or CD69(-/-)CD45RB(high) CD4 T cells. CD69 expression by CD4 T cells is induced by the intestinal microflora, oral delivery of specific Ag, and type I IFN (IFN-I) signals. CD4 T cells from CD69(-/-) animals produce higher amounts of the proinflammatory cytokines IFN-γ, TNF-α, and IL-21, whereas the production of TGF-β1 is decreased. CD69-deficient CD4 T cells showed reduced potential to differentiate into Foxp3(+) regulatory T cells in vivo and in vitro. The transfer of CD69(-/-)CD45RB(high) CD4 T cells into RAG(-/-) hosts induced an accelerated colitis. Oral tolerance was impaired in CD69(-/-) and IFN-I receptor 1-deficient mice when compared with B6 and OT-II × RAG(-/-) animals. Polyinosinic-polycytidylic acid treatment of RAG(-/-) mice transplanted with B6 but not CD69(-/-) or IFN-I receptor 1-deficient CD45RB(high) CD4 T cells attenuated transfer colitis. CD69 deficiency led to the increased production of proinflammatory cytokines, reduced Foxp3(+) regulatory T cell induction, impaired oral tolerance, and more severe colitis. Hence, the activation Ag CD69 plays an important role in regulating mucosal immune responses.
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Affiliation(s)
- Katarina Radulovic
- Department of Internal Medicine I, University of Ulm, Ulm D-89081, Germany
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Small intestinal intraepithelial lymphocytes expressing CD8 and T cell receptor γδ are involved in bacterial clearance during Salmonella enterica serovar Typhimurium infection. Infect Immun 2011; 80:565-74. [PMID: 22144492 DOI: 10.1128/iai.05078-11] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The intestinal immune system is crucial for the maintenance of mucosal homeostasis and has evolved under the dual pressure of protecting the host from pathogenic infection and coexisting with the dense and diverse commensal organisms in the lumen. Intestinal intraepithelial lymphocytes (iIELs) are the first element of the host T cell compartment available to respond to oral infection by pathogens. This study demonstrated that oral infection by Salmonella enterica serovar Typhimurium promoted the expansion of iIELs, particularly CD8(+) TCRγδ(+) IELs, enhanced expression of NKG2D on iIELs, increased expression of MULT1, and decreased expression of Qa-1 by intestinal epithelial cells (IECs), leading to activation of, particularly, CD8(+) TCRγδ(+) iIELs and cytolytic activity against S. Typhimurium-infected IECs. Blockade of NKG2D recognition or depletion of TCRγδ(+) cells using a depleting monoclonal antibody significantly attenuated the clearance of S. Typhimurium in the intestine and other tissues. This study suggests that iIELs, particularly CD8(+) TCRγδ(+) iIELs, play important roles in the detection of pathogenic bacteria and eradication of infected epithelial cells and, thus, provide protection against invading pathogens. These data further our understanding of the mechanisms by which the immune system of the intestinal mucosa discriminates between pathogenic and commensal organisms.
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The role of the intestinal context in the generation of tolerance and inflammation. Clin Dev Immunol 2011; 2012:157948. [PMID: 21949668 PMCID: PMC3178197 DOI: 10.1155/2012/157948] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 07/28/2011] [Indexed: 01/01/2023]
Abstract
The mucosal surface of the intestine alone forms the largest area exposed to exogenous antigens as well as the largest collection of lymphoid tissue in the body. The enormous amount of nonpathogenic and pathogenic bacteria and food-derived antigens that we are daily exposed sets an interesting challenge to the immune system: a protective immune activity must coexist with efficient regulatory mechanisms in order to maintain a health status of these organisms. This paper discusses how the immune system assimilates the perturbations from the environment without generating tissue damage.
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Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol 2011; 11:445-56. [PMID: 21681197 PMCID: PMC3140792 DOI: 10.1038/nri3007] [Citation(s) in RCA: 489] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.
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Affiliation(s)
- Hilde Cheroutre
- Laboratory of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
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Natural killer cells recognize friend retrovirus-infected erythroid progenitor cells through NKG2D-RAE-1 interactions In Vivo. J Virol 2011; 85:5423-35. [PMID: 21411527 DOI: 10.1128/jvi.02146-10] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Natural killer (NK) cells function as early effector cells in the innate immune defense against viral infections and also participate in the regulation of normal and malignant hematopoiesis. NK cell activities have been associated with early clearance of viremia in experimental simian immunodeficiency virus and clinical human immunodeficiency virus type 1 (HIV-1) infections. We have previously shown that NK cells function as major cytotoxic effector cells in vaccine-induced immune protection against Friend virus (FV)-induced leukemia, and NK cell depletion totally abrogates the above protective immunity. However, how NK cells recognize retrovirus-infected cells remains largely unclear. The present study demonstrates a correlation between the expression of the products of retinoic acid early transcript-1 (RAE-1) genes in target cells and their susceptibility to killing by NK cells isolated from FV-infected animals. This killing was abrogated by antibodies blocking the NKG2D receptor in vitro. Further, the expression of RAE-1 proteins on erythroblast surfaces increased early after FV inoculation, and administration of an RAE-1-blocking antibody resulted in increased spleen infectious centers and exaggerated pathology, indicating that FV-infected erythroid cells are recognized by NK cells mainly through the NKG2D-RAE-1 interactions in vivo. Enhanced retroviral replication due to host gene-targeting resulted in markedly increased RAE-1 expression in the absence of massive erythroid cell proliferation, indicating a direct role of retroviral replication in RAE-1 upregulation.
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Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R, Dinis-Ribeiro M, Leite-Moreira AF. Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets 2010; 14:347-68. [PMID: 20146632 DOI: 10.1517/14728221003642027] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPORTANCE OF THE FIELD Toll-like receptors (TLRs) are innate immunity receptors that recognize several different antigens, initiating immunological/inflammatory responses. Recent evidence associates numerous pathophysiological processes and diseases with dysregulated activation of these receptors, conferring a potential therapeutic value to their modulation. AREAS COVERED IN THIS REVIEW The aim of this systematic review that covers literature from the past 10 years is to address the role of TLRs in the pathophysiology of gastrointestinal (GI) diseases as well as the therapeutic potential of modulating TLRs' signaling pathways in GI pathology. WHAT THE READER WILL GAIN This review shows that TLRs play an important role in the pathophysiology of several GI diseases and that modulating TLRs signaling pathways may have an enormous therapeutic potential. Different methods for modulation of TLRs' activity in GI tract, with direct agonists/antagonists but also with non-specific substances, like antibiotics or probiotics, are presented. TAKE HOME MESSAGE Even though TLRs modulators have been used for therapy in some GI diseases, further research, particularly in humans, is needed in order to establish the precise role of the different TLRs in the diverse GI diseases and to motivate clinical trials that consider TLRs as therapeutic targets in GI pathology.
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Affiliation(s)
- Pedro Pimentel-Nunes
- Department of Physiology, Cardiovascular Research & Development Unit, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319, Portugal.
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Jabri B, Sollid LM. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 2009; 9:858-70. [PMID: 19935805 DOI: 10.1038/nri2670] [Citation(s) in RCA: 235] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Coeliac disease is an inflammatory disorder with autoimmune features that is characterized by destruction of the intestinal epithelium and remodelling of the intestinal mucosa following the ingestion of dietary gluten. A common feature of coeliac disease and many organ-specific autoimmune diseases is a central role for T cells in causing tissue destruction. In this Review, we discuss the emerging hypothesis that, in coeliac disease, intestinal tissue inflammation--induced either by infectious agents or by gluten--is crucial for activating T cells and eliciting their tissue-destructive effector functions.
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Affiliation(s)
- Bana Jabri
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
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Tian Z. Innate immune recognition and regulation in liver injury: A brief report from a series of studies. Sci Bull (Beijing) 2009. [DOI: 10.1007/s11434-009-0252-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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