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）：炎症性肠病 (IBD) 的两种最常见形式，即克罗恩病和溃疡性结肠炎，影响着美国约 140 万人。 IBD 的病因尚不清楚，但针对共生微生物群的异常先天性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）抗原呈递细胞网络极其复杂，其中包含巨噬细胞和树突状细胞（DC）的几个子集，这些子集在体内平衡和炎症期间沿着小鼠肠道的长度在表型、功能和区域上有所不同。我们的研究表明，表达稳态 CX3CR1 的 LP 巨噬细胞是 IL-10 的主要产生者，并且擅长以 IL-10 和视黄酸依赖性方式促进 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 亚群则表达 TGF？和 IL-6 并在体外和体内驱动 Th17 细胞的分化。最近，我们发现 CX3CR1/CX3CL1 轴对于维持 LP 巨噬细胞稳态、细菌易位和限制致结肠炎 Th17 反应至关重要。在这些研究过程中，我们发现 CX3CR1 缺陷会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 中充满了表达 Ly6C 的炎症巨噬细胞的独特子集。据了解，表达CX3CR1的抗炎性LP巨噬细胞在健康肠道中大量存在，而表达Ly6C的促炎性LP巨噬细胞在发炎肠道中占主导地位，我们对这两个子集进行了DNA微阵列分析，以确定可能作为治疗目的的候选基因。微阵列比较的结果是，我们鉴定出了新的 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 的发病机制相关，但 IL-36? 的表达和功能与实验和人类 IBD 的发病机制相关。在肠道中的作用完全未被探索。我们令人兴奋的初步数据表明 IL-36？促进 LP 巨噬细胞和 DC 活化，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性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。