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.

抽象的 克罗恩病和溃疡性结肠炎，两种最常见的炎症性肠病（IBD）形式影响 美国约有150万人。 IBD的病因尚不清楚，但是失调 据信针对菌群的先天和适应性免疫调查是疾病的基础 发病。目前，针对促炎性细胞因子（例如TNF和IL-12/23）的生物疗法具有 表现出巨大的希望。但是，关于免疫细胞和因素，还有很多尚待理解的 为IBD做出贡献，以及如何控制它们以改善人类健康。我们最近的工作，资助 该申请旨在建立的2018年已经揭示了IL-的重要而复杂的贡献 36/IL-36受体（IL-36R）轴是对先天和适应性粘膜免疫调查和肠道的调节 炎。我们是第一个报告IL-36配体在急性和慢性实验中表达的人 小鼠和人类IBD期间的结肠炎。我们已经表明，IL-36配体，尤其是IL-36G，由 响应小鼠肠屏障损伤的炎症巨噬细胞。生物学后果 急性肠损伤期间通过IL-36R发出信号，这可能是IL-1相关的细胞因子轴的预期 包括增强的炎症。令人惊讶的是，我们观察到在该期间还需要IL-36R信号传导 最佳嗜中性粒细胞募集和IL-23/IL-22表达的急性结肠损伤的分辨率阶段。这些 结果导致我们包括IL-36/IL-36R轴不仅调节免疫球的募集和注射，还调节 而且还保护与IL-22和抗微生物胡椒体相关的维修过程。那，我们推测 炎症和屏障保护紧密地交织在一起。超越先天免疫反应，发出信号 通过IL-36R也对CD4+ T细胞具有潜在的影响。我们发表的工作表明IL-36配体 潜在地抑制诱导的调节T细胞（ITREG）途径，而同时增强效应子Th 回答。我们的研究表明，这些发现的体内相关性证明了TH的严重程度降低 在IL-36R或IL-36G缺乏的小鼠中依赖细胞的恶唑酮结肠炎。总的来说，我们的发现突出了背景 - 肠道中IL-36/IL-36R途径的依赖性致病和受保护的贡献。我们的新 初步数据表明：1）在无细菌小鼠的急性屏障损伤和 可通过细菌配体在体外诱导； 2）在IL-36R缺陷中改变了菌群的组成 小鼠在稳态和急性屏障损伤之后； 3）T细胞和树突状的IL-36R表达 细胞参与增强炎症信号传导； 4）在特定中可以抑制炎性细胞因子 使用siRNA加载的纳米颗粒中的肠中的细胞，同时提供亲休息的因子 例如IL-22。这些数据为进一步研究这一令人兴奋而重要的研究领域奠定了基础。

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