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，在美国影响了大约140万人。IBD的病因尚不清楚，但针对共生菌群的异常先天和适应性免疫反应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非常复杂的，有几个巨噬细胞和树突状细胞（dc）亚群，它们在体内平衡和炎症期间沿小鼠肠道长度呈现不同的表型、功能和区域。我们的研究发现，稳态表达cx3cr1的LP巨噬细胞是IL-10的主要产生者，并且擅长以IL-10和视黄酸依赖的方式促进Foxp3+ Treg细胞的分化。相反，我们发现表达cd103的LP DC是IL-10的不良生产者，CD11b+ LP DC亚群表达TGF？和IL-6，并在体内和体外驱动Th17细胞的分化。最近，我们发现CX3CR1/CX3CL1轴对于维持LP巨噬细胞稳态、细菌易位和限制结肠炎Th17反应至关重要。在这些研究的过程中，我们发现CX3CR1缺陷导致稳定状态下常驻LP巨噬细胞的损失，然而在结肠炎期间，LP被一种独特的表达ly6c的炎性巨噬细胞亚群填充。了解到表达cx3cr1的抗炎LP巨噬细胞在健康肠道中丰富，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。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Ly6C+ LP巨噬细胞中最优先表达的细胞因子。IL-1细胞因子家族的几个成员，包括IL-1？, il - 1 ?IL-18和IL-33与实验和人类IBD的发病机制有关，但IL-36的表达和功能在肠道中完全没有被研究过。我们激动人心的初步数据表明IL-36？促进LP巨噬细胞和DC的激活，并且在结肠炎期间阻断IL-36R可改善疾病。在本提案中，我们将具体确定IL-36配体在肠道炎症期间调节先天和适应性免疫反应中的作用。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.