权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of the prostaglandin D2 receptor CRTH2 in helminth-induced type 2 inflammation in the intestine

前列腺素 D2 受体 CRTH2 在蠕虫引起的肠道 2 型炎症中的作用

基本信息

批准号：
10228717
负责人：
Elia D Tait Wojno
金额：
$ 43.23万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228717
关键词：
Address Adoptive Transfer Affect Allergic Anti-Inflammatory Agents Binding Bone Marrow CCL4 gene Cells Chimera organism Coupled Data Development Disease Dopamine D2 Receptor Drug Targeting Drug usage Epithelial Epithelial Cells Equilibrium Generations Helminths Hookworms Immune Immune response Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukins Intestines Knowledge Lead Lipids Lung Inflammation Lung diseases Lymphoid Lymphoid Cell Modeling Morbidity - disease rate Mucins Mucous body substance Mus Nippostrongylus Organoids Parasites Pathologic Pathology Pathway interactions Phenotype Play Population Production Prostaglandin D2 Proteins Role Shapes Signal Pathway Signal Transduction Small Intestines Source Symptoms Testing Th2 Cells Work base cytokine experimental study fMet-Leu-Phe receptor helminth infection immune activation in vivo inflammatory disease of the intestine inhibitor/antagonist intestinal epithelium loss of function mast cell mouse model novel therapeutics prevent receptor response

项目摘要

PROJECT SUMMARY Intestinal helminth parasites infect billions worldwide. Mammalian hosts mount a Type 2 inflammatory response to infection, which is characterized by immune cell activation and intestinal epithelial cell mucus secretion that lead to worm expulsion but can also cause pathological excess mucus production. Previous work has focused on how host-derived proteins called cytokines control Type 2 inflammation, but other factors such as the lipid prostaglandin D2 (PGD2) are also produced during infection. PGD2 promotes Type 2 allergic lung inflammation by binding to CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). However, how the PGD2-CRTH2 pathway interacts with cytokines to regulate Type 2 inflammation during intestinal helminth infection is unclear. Our preliminary studies revealed that following infection with the helminth Nippostrongylus brasiliensis, CRTH2-deficient mice had decreased Type 2 immune activation compared to controls, but surprisingly also had increased epithelial mucin responses and accelerated worm clearance. This phenotype was also observed in infected bone marrow chimeric mice in which only non- hematopoietic cells lacked CRTH2, suggesting that the PGD2-CRTH2 pathway suppresses intestinal epithelial cell mucus responses. Notably, how PGD2 production is regulated is unclear. The epithelial cell-derived cytokine interleukin (IL)-33, which activates immune cells during helminth infection, elicits PGD2 production from mast cells in vitro. Thus, IL-33 may activate the PGD2-CRTH2 pathway in vivo. Our preliminary studies showed that following IL-33 treatment, CRTH2-deficient mice had impaired population expansion of IL-33- responsive group 2 innate lymphoid cells compared to controls, suggesting that optimal responses to IL-33 in vivo require CRTH2. Together, these data provoke the central hypothesis that during helminth infection, IL-33 activates the PGD2-CRTH2 pathway to balance Type 2 inflammatory responses, expelling worms efficiently while limiting pathology. To test this hypothesis, we propose 2 Specific Aims. Aim 1 will test if PGD2 acts directly on small intestinal epithelial cells to inhibit mucin production during Type 2 inflammation, dependent on CRTH2, using small intestinal organoid cultures and a new mouse model that allows for deletion of CRTH2 only in intestinal epithelial cells. Aim 2 will test how IL-33 regulates PGD2 production by mast cells to shape immune responses during Type 2 inflammation, using gain- and loss-of-function experiments, adoptive transfer approaches, and bone marrow chimeric mice coupled with N. brasiliensis infection. These data will support the generation of a new paradigm of helminth-induced Type 2 intestinal inflammation that incorporates the effects of PGD2 and CRTH2, and will inform the development and use of drugs that target the PGD2-CRTH2 pathway to treat diseases associated with Type 2 inflammation.

项目总结