Intestinal Antigen Presenting Cells and Mucosal Immunity

描述（由申请人提供）：两种最常见的炎症性肠病（IBD），克罗恩病和溃疡性结肠炎，影响美国约140万人。IBD的病因尚不清楚，但针对肠道微生物群的异常先天性和适应性免疫应答被认为是疾病发病机制的基础。我们已经证明，肠道固有层（LP）抗原呈递细胞网络是令人难以置信的复杂的巨噬细胞和树突状细胞（DC）的几个子集，不同的表型，功能，和区域沿着小鼠肠道的长度在稳态和炎症。我们的研究表明，稳态CX 3CR 1表达的LP巨噬细胞是IL-10的主要生产者，并擅长以IL-10和视黄酸依赖性方式促进Foxp 3 + Treg细胞分化。相反，我们发现，表达CD 103的LP DC是IL-10的穷人生产者和CD 11b + LP DC亚群表达TGF？和IL-6，并在体外和体内驱动Th 17细胞的分化。最近，我们进行了新的观察，CX 3CR 1/CX 3CL 1轴是至关重要的维持LP巨噬细胞稳态，细菌易位，并限制colitogenic Th 17反应。在这些研究的过程中，我们发现CX 3CR 1缺乏导致稳态中驻留的LP巨噬细胞的损失，然而在结肠炎期间，LP由表达Ly 6C的炎性巨噬细胞的独特子集占据。有了CX 3CR 1表达的抗炎LP巨噬细胞在健康肠道中丰富，而Ly 6C表达的促炎LP巨噬细胞在发炎的肠道中占主导地位的知识，我们对这两个子集进行了DNA微阵列分析，以鉴定可能用于治疗目的的候选基因。作为微阵列比较的结果，我们确定了新的IL-1家族成员IL-36？作为Ly 6C + LP巨噬细胞中最优先表达的细胞因子。细胞因子IL-1家族的几个成员，包括IL-1？，IL-1？，IL-18和IL-33与实验性和人类IBD的发病机制有关，然而IL-36的表达和功能？是完全未知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活化，并且在结肠炎期间阻断IL-36 R可改善疾病。在这个建议中，我们将具体确定IL-36配体在肠道炎症过程中调节先天性和适应性免疫反应的作用。这些研究的结果将对治疗人类IBD具有潜在的治疗价值。

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.