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Function of NLRP3 in regulatory T cell-mediated control of intestinal homeostasis

NLRP3 在调节性 T 细胞介导的肠道稳态控制中的功能

基本信息

批准号：
10748891
负责人：
RASIKA PATKAR
金额：
$ 4.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748891
关键词：
Ablation Affect Anti-Inflammatory Agents Antigens Autoimmune Bacterial Infections Biological Bone Marrow CASP1 gene CD3 Antigens Caspase Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cellular biology Chimera organism Chronic Citrobacter rodentium Complex Cytoplasm Data Development Disease Disease model Enteral Exhibits FOXP3 gene Food Frequencies Future Genes Homeostasis Human IL17 gene IL18 gene Immune Immune response Immunity Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-1 Interleukin-1 beta Intestinal Diseases Intestines Knockout Mice Lymphoid Measures Mediating Microbe Modeling Molecular Multiprotein Complexes Mus Natural Immunity Nature Pathologic Pathway interactions Physiological Play Production Proteins Regulation Regulatory T-Lymphocyte Reporting Role Sorting System T cell differentiation T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissues Transcript adaptive immunity commensal microbes constitutive expression cytokine effective therapy gain of function gut inflammation immunoregulation insight intestinal homeostasis loss of function mouse model novel response transcription factor transcriptome sequencing

项目摘要

Project Summary The inflammasomes are cytoplasmic multi-protein complexes that can sense and be activated by microbes or tissue damage, which then leads to the activation of caspase-mediated inflammatory pathways involving the release of cytokines IL-1β and IL-18. Although the pro-inflammatory role of inflammasomes have been well established in innate immune cells, recently, several studies have uncovered a role for different inflammasome components in regulating many different T cell responses, a key part of adaptive immunity. Specifically, a subset of T cells called regulatory T cells (Tregs), which are known for their ability to suppress immune responses and inflammation, were shown to be affected by their cell intrinsic inflammasome components. Even though the critical role of Tregs in establishing tolerance to a wide range of innocuous foreign antigens from commensal microbes and food in the gut has long been well-recognized, the function of the NLRP3 inflammasome in Treg-mediated control of intestinal homeostasis remains an open question. Based on preliminary data, it was hypothesized that NLRP3/inflammasome could serve as an integral determinant in controlling Treg biology and that induction of NLRP3 in intestinal Tregs would be specifically required for their control of Th17 responses in the intestine. To test this hypothesis, the first aim will elucidate the function of NLRP3 in controlling Treg biology in the gut in heath and disease using both loss-of-function and gain-of- function approaches through employing two novel mouse models that have been recently generated in the lab: mice with Treg-specific deletion of NLPR3 and mice with Treg-specific expression of constitutively active NLRP3. Two different Th17-dependent disease models: anti-CD3 induced intestinal inflammation and Citrobacter rodentium infection model will be employed. As such, the biological impact of NLRP3 depletion or constitutive activation in Tregs on the other immune cells in the intestinal system under both physiological and pathological conditions will be elucidated. In the second aim, the molecular mechanisms underlying NLRP3- mediated control of Treg biology will be investigated. First, as IL-1b, a component of the NLRP3/inflammasome pathway was also found to be selectively induced in intestinal Tregs under inflammation, I will determine the potential role of Treg-derived IL-1b in controlling intestinal homeostasis. Next, the potential involvement of inflammasome-independent vs. –dependent mechanism underlying NLRP3-mediated Treg biology will also be examined. Finally, as the heterogeneous nature of Tregs is now well appreciated, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) studies will be conducted to determine if there is a specific subset of Tregs that expresses NLRP3 or whether NLRP3 induction is a common feature for all intestinal Tregs under inflammation. Collectively, this study will provide mechanistic insights into the underappreciated anti-inflammatory role of NLRP3 in intestinal Tregs and will undoubtedly facilitate the development of future therapeutics for inflammatory bowel disease and other human intestinal disorders.

项目总结