IL-36 cytokines and gut immunity

IL-36 细胞因子和肠道免疫

• 批准号: 10534223
• 负责人: Timothy L Denning
• 金额: $ 41.88万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-24 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534223
• 关键词: Acute; Affect; Antibodies; Area; Biological; Biological Response Modifier Therapy; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cells; Chronic; Colitis; Colon; Colon Injury; Complex; Crohn' s disease; Data; Data Set; Dendritic Cells; Disease; Epithelium; Etiology; Funding; Germ-Free; Health; Hematopoietic; Human; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Interleukin-1; Interleukin-12; Intestinal Diseases; Intestines; Investigation; Ligands; Link; Macrophage; Mediating; Mucosal Immune Responses; Mus; Neutrophil Infiltration; Oxazolone; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Phase; Process; Publishing; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Resolution; Role; Severities; Signal Transduction; Small Interfering RNA; T-Lymphocyte; TNF gene; Testing; Therapeutic; Ulcerative Colitis; United States; Work; adaptive immune response; antimicrobial peptide; cell type; chronic inflammatory disease; cytokine; defined contribution; gut inflammation; gut microbiome; improved; in vivo; insight; interleukin-22; interleukin-23; intestinal barrier; microbial; microbiome composition; microbiota; murine colitis; nanoparticle; nanoparticle delivery; novel; protective effect; protective factors; receptor; receptor expression; recruit; repaired; response; restoration; targeted treatment

Abstract Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease (IBD), affect approximately 1.5 million people in the United States. The etiology of IBD remains unclear, however dysregulated innate and adaptive immune responses directed towards the microbiota are believed to underlie disease pathogenesis. Currently biologic therapies targeting pro-inflammatory cytokines such as TNF and IL-12/23 have shown great promise. However, much remains to be understood regarding the immune cells and factors that contribute to IBD and how they can be controlled to improve human health. Our recent work, funded through 2018, which this application seeks to build upon, has unraveled important and complex contributions of the IL- 36/IL-36 receptor (IL-36R) axis in the regulation of innate and adaptive mucosal immune responses and intestinal inflammation. We were the first to report that IL-36 ligands are expressed during acute and chronic experimental colitis in mice and during human IBD. We have shown that IL-36 ligands, particularly IL-36g, are secreted by inflammatory macrophages in response to intestinal barrier damage in mice. The biological consequences of signaling through IL-36R during acute intestinal damage, as might be expected of an IL-1-related cytokine axis, include enhanced inflammation. Strikingly, we observed that IL-36R signaling is also required during the resolution phase of acute colonic injury for optimal neutrophil recruitment and IL-23/IL-22 expression. These results led us to conclude that the IL-36/IL-36R axis regulates not only immune cell recruitment and inflammation, but also protective repair processes that are linked to IL-22 and anti-microbial peptides. Thus, we speculate that inflammation and barrier protection are intimately intertwined. Beyond innate immune responses, signaling through IL-36R also has potent effects on CD4+ T cells. Our published work has demonstrated that IL-36 ligands potently inhibit the induced regulatory T cell (iTreg) pathway, while concomitantly augmenting effector Th responses. The in vivo relevance of these findings is evidenced by our studies showing reduced severity of Th cell-dependent oxazolone colitis in mice deficient in IL-36R or IL-36g. Collectively, our findings highlight context- dependent pathogenic and protective contributions of the IL-36/IL-36R pathway in the intestine. Our new preliminary data demonstrate that: 1) IL-36g is not induced during acute barrier damage in germ-free mice and can be induced in vitro by bacterial ligands; 2) The composition of the microbiota is altered in IL-36R-deficient mice both in the steady-state and following acute barrier damage; 3) IL-36R expression by T cells and dendritic cells is involved in augmenting inflammatory signaling; and 4) Inflammatory cytokines can be inhibited in specific cells in the intestine using siRNA-loaded nanoparticles while simultaneously delivering pro-restitutive factors such as IL-22. These data set the stage for further investigation into this exciting and important area of research.

摘要

项目成果

IL-36R signaling integrates innate and adaptive immune-mediated protection against enteropathogenic bacteria.

IL-36R 信号传导整合了先天性和适应性免疫介导的针对肠道致病细菌的保护。

• DOI: 10.1073/pnas.2004484117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Ngo,VuL;Abo,Hirohito;Kuczma,Michal;Szurek,Edyta;Moore,Nora;Medina-Contreras,Oscar;Nusrat,Asma;Merlin,Didier;Gewirtz,AndrewT;Ignatowicz,Leszek;Denning,TimothyL
• 通讯作者: Denning,TimothyL