Intestinal Antigen Presenting Cells and Mucosal Immunity

肠道抗原呈递细胞和粘膜免疫

• 批准号: 8727543
• 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/8727543
• 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; Hematopoietic; Homeostasis; Human; ITGAM gene; Immune response; 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; cytokine; immune activation; in vivo; insight; interleukin-23; macrophage; member; mouse model; novel; public health relevance; receptor; research study; response; therapeutic development; therapeutic target; 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（由申请人提供）：在美国，炎症性肠病（IBD）的两种最常见形式，克罗恩病和溃疡性结肠炎，影响了美国约140万人。 IBD的病因尚不清楚，但据信针对共生微生物群的异常和适应性免疫反应是疾病发病机理的基础。我们已经证明，肠道固有层（LP）抗原呈现细胞网络与几种巨噬细胞和树突状细胞（DC）非常复杂，它们在稳态和炎症过程中沿着表型，功能和区域上沿着小鼠肠的长度有所不同。我们的研究表明，稳态表达CX3CR1的LP巨噬细胞是IL-10的主要生产国，并且擅长以IL-10和视黄酸依赖性方式促进Foxp3+ Treg细胞分化。相反，我们发现表达CD103的LP DC是IL-10的较差生产国，CD11b+ LP DC子集表达TGF？和IL-6，并在体外和体内驱动Th17细胞的分化。最近，我们对CX3CR1/CX3CL1轴进行了新的观察，这对于维持LP巨噬细胞稳态，细菌易位和限制了colititic 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居民LP巨噬细胞的丧失，但是在结肠炎期间，LP在LP中受到了表达Ly6c的炎症性巨噬细胞的独特子集。随着人们的了解，表达CX3CR1的抗炎LP巨噬细胞在健康的肠道中很丰富，而表达Ly6C的促炎LP巨噬细胞主导了发炎的肠道，我们对这两个子集进行了DNA微阵列分析，以识别这两个子集以识别可能针对更可取的候选基因。由于微阵列比较，我们确定了新型的IL-1家族成员IL-36？作为在LY6C+ LP巨噬细胞中最优先表达的细胞因子的最高表达。 IL-1细胞因子家族的几个成员，包括IL-1？，IL-1？，IL-18和IL-33与实验和人IBD的发病机理有关，但是IL-36的表达和功能？在肠中完全没有探索。我们令人兴奋的初步数据表明IL-36？促进LP巨噬细胞和直流激活，以及结肠炎期间IL-36R的阻塞可改善疾病。在此提案中，我们将特别确定IL-36配体在调节肠道炎症过程中先天和适应性免疫反应中的作用。这些研究的结果将具有治疗人IBD的潜在治疗价值。