Innate Immune Cell Regulation of Mucosal Homeostasis

先天免疫细胞对粘膜稳态的调节

基本信息

批准号：
9087834
负责人：
Amlan Biswas
金额：
$ 15.19万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087834
关键词：
Actins Anti-Inflammatory Agents Anti-inflammatory Antigens Bacteria Bayesian Analysis Biopsy Bone Marrow CD4 Positive T Lymphocytes Cell physiology Cells Citrobacter rodentium Complex Cytoskeletal Proteins Data Defect Dendritic Cells Development Disease remission Disease susceptibility Eczema Environment Epithelial Gene Expression Generations Genes Goals Homeostasis Human IL10 gene Immune Immune Tolerance Immune response Immune system Immunologic Deficiency Syndromes In Vitro Infection Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukin-10 Interleukin-17 Intestinal Mucosa Intestines K-Series Research Career Programs Knowledge Lamina Propria Lead Link Lymphoid Cell Maintenance Mediating Mentors Mucosal Immune Responses Mus Mutation Myeloid Cells Patients Play Population Predisposition Production Protein Deficiency Proteins Publishing Recurrence Regulation Regulatory T-Lymphocyte Reporting Research Role STAT3 gene Structure Surface T cell response Testing Thrombocytopenia Training Wiskott-Aldrich Syndrome commensal microbes cytokine disorder risk gut microbiota in vivo interleukin-22 intestinal homeostasis loss of function mutation macrophage member microbial community novel therapeutic intervention prevent public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): The intestinal mucosal surface is continuously exposed to microbial communities and intestinal homeostasis is dependent on host barrier function and the establishment and persistence of well- regulated immune responses. Innate immune cells play critical roles in the maintenance of mucosal homeostasis by establishing immune tolerance. A recent study identified an inflammatory bowel disease (IBD) causal sub-network of genes (IL10, ARC, NOD2, HCK, WAS, NCKAP1L), which were highly enriched in bone-marrow derived macrophages and predicted to have a role in anti-inflammatory macrophage function. Wiskott-Aldrich syndrome protein (WAS) was one of the genes identified within this sub-network, along with HCK, a protein that interacts with Wiskott-Aldrich syndrome protein (WASP). Moreover, up to 10% of Wiskott-Aldrich syndrome patients develop IBD. We have shown that WASP-deficiency in mice, when limited to innate immune cells, is sufficient to render normal wild-type CD4+ T cells colitogenic with associated defects in tolerogenic dendritic cell (DC) subsets. While WASP may have regulatory functions in DCs, most exciting is our preliminary data presented within this proposal showing that WASP-deficiency is associated with marked abnormalities in anti-inflammatory macrophage differentiation and function. We found that WASP-deficiency is associated with defects in generation of tolerogenic macrophage in both mice and humans leading to aberrant pro-inflammatory cytokine secretion. Another integral part of the innate immune system involved in maintaining mucosal homeostasis is group 3 innate lymphoid cells (ILC3). These cells secrete IL-17 and IL-22, which are important for barrier integrity and have also been shown to regulate intestinal tolerogenic DC and MΦ populations, and CD4+ T cell responses to commensal bacteria. We found that in the absence of WASP, ILC3 function is aberrant. Therefore, We hypothesize that WASP-mediated regulation of anti- inflammatory MΦ and ILC3 function is critical for the maintenance of intestinal homeostasis. To test this we will first delineate the 1) intrinsic role of WASP in regulating anti-inflammatory MΦ function and define the mechanism of immune tolerance; second, we will uncover the 2) intrinsic role of WASP in ILC3 and their associated regulation of intestinal homeostasis; and finally we 3) investigate the role of WASP in anti-inflammatory MΦ and ILC3 development/function in humans.

描述（由适用提供）：肠粘膜表面不断暴露于微生物群落，肠内稳态骨质骨骨化取决于宿主屏障功能，以及受调节良好的免疫调查的建立和持久性。先天免疫细胞通过建立免疫耐受性在维持粘膜稳态中起关键作用。最近的一项研究确定了基因（IL10，ARC，NOD2，HCK，NCKAP1L）的炎症性肠病（IBD）因果子网络，该因子在骨髓衍生的巨噬细胞中高度富集，并预测在抗炎性巨噬细胞功能中起作用。 Wiskott-Aldrich综合征蛋白（WAS）是该子网络中鉴定的基因之一，HCK是一种与Wiskott-Aldrich综合征蛋白（WASP）相互作用的蛋白质。此外，多达10％的Wiskott-Aldrich综合征患者正在发展IBD。我们已经表明，如果仅限于先天免疫细胞的小鼠中的黄蜂缺乏足以使野生型CD4+ T细胞具有正常的野生型CD4+ T细胞的伴有耐受性树突状细胞（DC）亚群的相关缺陷。尽管WASP可能在DC中具有调节功能，但最令人兴奋的是我们在该提案中介绍的初步数据，表明黄蜂缺陷与抗炎巨噬细胞分化和功能的明显异常有关。我们发现，WASP缺陷与小鼠和人类的耐巨噬细胞产生缺陷有关，导致异常的促炎细胞因子分泌。维持粘膜稳态涉及的先天免疫系统的另一个组成部分是3组先天淋巴样细胞（ILC3）。这些细胞秘密IL-17和IL-22，对屏障完整性很重要，并且还发现在没有黄蜂的情况下，ILC3功能是异常的。因此，我们假设黄蜂介导的抗炎Mφ和ILC3功能的调节对于维持肠内稳态至关重要。为了测试这一点，我们将首先描述1）黄蜂在调节抗炎Mφ功能中的内在作用，并定义免疫耐受的机理；其次，我们将发现2）黄蜂在ILC3中的内在作用及其相关的肠内稳态调节；最后，我们3）研究黄蜂在人类中的抗炎Mφ和ILC3发育/功能中的作用。