Intestinal Antigen Presenting Cells and Mucosal Immunity

肠道抗原呈递细胞和粘膜免疫

• 批准号: 9099831
• 负责人: Timothy L Denning
• 金额: $ 32.19万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099831
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Bacterial Translocation; Biological Process; Bone Marrow; CD4 Positive T Lymphocytes; CX3CL1 gene; Candidate Disease Gene; Cell Differentiation process; Cells; Chimera organism; Chronic; Colitis; Complex; Crohn' s disease; DNA Microarray Chip; Data; Dendritic Cells; Dendritic cell activation; Disease; Epithelial Cells; Etiology; Family; Family member; Genetic; Health; Hematopoietic; Homeostasis; Human; ITGAM gene; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-18; Interleukin-6; Intestines; Investigation; Knowledge; Lamina Propria; Lead; Length; Ligands; Microarray Analysis; Molecular; Mucosal Immunity; Mus; Outcome Study; Pathogenesis; Production; Regulatory T-Lymphocyte; Role; Signal Transduction; Stimulus; T cell differentiation; Testing; Therapeutic; Time; Toll-like receptors; Tretinoin; Ulcerative Colitis; United States; adaptive immunity; cytokine; immune activation; in vivo; insight; interleukin-23; macrophage; member; microbiota; mouse model; novel; receptor; research study; response; targeted treatment; therapeutic development; treatment strategy

DESCRIPTION (provided by applicant): The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate and adaptive immune responses directed towards commensal microbiota are believed to underlie disease pathogenesis. We have demonstrated that the intestinal lamina propria (LP) antigen presenting cell network is incredibly complex with several subsets of macrophages and dendritic cells (DCs) that differ phenotypically, functionally, and regionally along the length of the mouse intestine during homeostasis and inflammation. Our investigations revealed that steady state CX3CR1-expressing LP macrophages are major producers of IL-10 and are adept at promoting Foxp3+ Treg cell differentiation in an IL-10- and retinoic acid-dependent manner. Conversely, we discovered that CD103-expressing LP DCs are poor producers of IL-10 and the CD11b+ LP DC subset expresses TGF? and IL-6 and drives the differentiation of Th17 cells both in vitro and in vivo. More recently, we made the novel observation that the CX3CR1/CX3CL1 axis is critically important for maintaining LP macrophage homeostasis, bacterial translocation, and limiting colitogenic Th17 responses. In the course of these studies we discovered that CX3CR1 deficiency leads to a loss of resident LP macrophages in the steady state, however during colitis the LP is populated by a unique subset of Ly6C-expressing inflammatory macrophages. With the knowledge that CX3CR1-expressing anti-inflammatory LP macrophages are abundant in the healthy intestine, while Ly6C-expressing pro-inflammatory LP macrophages dominate the inflamed intestine, we performed a DNA microarray analysis of these two subsets in order to identify candidate genes that may be targeted for therapeutic purposes. As a result of the microarray comparison, we identified the novel IL-1 family member IL-36? as the top most preferentially expressed cytokine in Ly6C+ LP macrophages. Several members of the IL-1 family of cytokines, including IL-1?, IL-1?, IL-18 and IL-33 are associated with the pathogenesis of experimental and human IBD, however the expression and function of IL-36? in the intestine is completely unexplored. Our exciting preliminary data demonstrate that IL-36? promotes LP macrophage and DC activation and that blocking of IL-36R during colitis ameliorates disease. In this proposal we will specifically determine the role of IL-36 ligands in modulating innate and adaptive immune responses during intestinal inflammation. The outcome of these studies will have potential therapeutic value for treating human IBD.

描述(申请人提供)：炎症性肠病(IBD)的两种最常见的形式，克罗恩病和溃疡性结肠炎，在美国大约有140万人受到影响。IBD的病因尚不清楚，但针对共生微生物区系的异常先天和获得性免疫反应被认为是疾病发病的基础。我们已经证明，肠道固有层(LP)抗原提呈细胞网络是令人难以置信的复杂的，含有几个亚群的巨噬细胞和树突状细胞(DC)，在动态平衡和炎症期间，这些细胞在表型、功能和局部上沿小鼠肠道长度不同。我们的研究表明，稳定表达CX3CR1的LP巨噬细胞是产生IL-10的主要细胞，并擅长以IL-10和视黄酸依赖的方式促进Foxp3+Treg细胞分化。相反，我们发现表达CD103的LP DC不能产生IL-10，而CD11b+LP DC亚群表达转化生长因子？和IL-6，并在体外和体内驱动Th17细胞的分化。最近，我们进行了新的观察，发现CX3CR1/CX3CL1轴对于维持LP巨噬细胞的动态平衡、细菌易位和限制致病性Th17反应至关重要。在这些研究过程中，我们发现CX3CR1缺乏导致稳定状态下常驻LP巨噬细胞的丢失，然而在结肠炎期间LP由一组独特的表达Ly6C的炎性巨噬细胞填充。了解到CX3CR1表达的抗炎LP巨噬细胞在健康肠道中大量存在，而表达Ly6C的促炎LP巨噬细胞在炎症肠道中占主导地位，我们对这两个亚群进行了DNA微阵列分析，以确定可能用于治疗目的的候选基因。通过芯片比对，我们鉴定出新的IL-1家族成员IL-36？作为最先在Ly6C+LP巨噬细胞中优先表达的细胞因子。IL-1家族中的几个成员，包括IL-1β、IL-1β、IL-18和IL-33与实验性和人类IBD的发病机制有关，但IL-36、IL-18和IL-33的表达和功能与IBD的发病机制密切相关。在肠道中是完全未被探索的。我们令人兴奋的初步数据表明，IL-36？促进LP巨噬细胞和DC的激活，在结肠炎期间阻断IL-36R可改善疾病。在这项建议中，我们将具体确定IL-36配体在调节肠道炎症期间的先天和获得性免疫反应中的作用。这些研究结果将对治疗人类IBD具有潜在的治疗价值。