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：
9986377
负责人：
Elia D Tait Wojno
金额：
$ 39.9万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9986377
关键词：
Address Adoptive Transfer Affect Allergic Anti-inflammatory 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 Cell Activation Immune response Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Inflammatory disease of the intestine 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 Source Symptoms Testing Th2 Cells Work base cytokine experimental study fMet-Leu-Phe receptor helminth infection in vivo inhibitor/antagonist 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.

项目摘要肠命中寄生虫在全球感染了数十亿。哺乳动物托管载有2型炎症对感染的反应，其特征是免疫细胞活化和肠上皮细胞粘液导致蠕虫驱逐的分泌，也可能导致病理过多的粘液产生。以前的工作重点是宿主衍生的蛋白如何称为Cytokines Control 2型炎症，但其他因素在感染期间还产生了脂质前列腺素D2（PGD2）。 PGD2促进2型过敏通过与CRTH2结合（趋化受体受体同型分子在Th2上表达的肺炎症）细胞）。但是，PGD2-CRTH2途径如何与细胞因子相互作用以调节2型炎症在肠蠕虫感染期间尚不清楚。我们的初步研究表明，感染了 Helminth Nippostrongylus brasiliensis，Crth2缺陷小鼠的2型免疫激活降低与对照组相比，但令人惊讶的是上皮粘蛋白反应增加并加速了蠕虫清除。在感染的骨髓嵌合小鼠中也观察到了这种表型造血细胞缺乏CRTH2，表明PGD2-CRTH2途径抑制了肠上皮细胞粘液反应。值得注意的是，如何调节PGD2的生产尚不清楚。上皮细胞衍生细胞因子白介素（IL）-33，在蠕虫感染期间激活免疫细胞，引起PGD2的产生来自肥大细胞的体外。因此，IL-33可以在体内激活PGD2-CRTH2途径。我们的初步研究结果表明，在IL-33治疗后，CRTH2缺陷小鼠的人群扩大IL-33-- 与对照组相比，响应迅速的第2组先天淋巴样细胞，表明对IL-33的最佳反应 Vivo需要CRTH2。这些数据共同引起了一个中心假设，即在蠕虫感染期间，IL-33 激活PGD2-CRTH2途径以平衡2型炎症反应，有效地排出蠕虫同时限制病理。为了检验这一假设，我们提出了2个具体目标。 AIM 1将测试PGD2是否行动直接在小肠上皮细胞上抑制2型炎症期间粘蛋白的产生，取决于 CRTH2，使用小肠癌培养物和新的小鼠模型，允许删除CRTH2 仅在肠上皮细胞中。 AIM 2将测试IL-33如何调节肥大细胞产生PGD2 使用功能丧失和功能丧失实验，收养转移的2型炎症期间的免疫反应接近，骨髓嵌合小鼠以及巴西氏猪笼草感染。这些数据将支持生成蠕虫诱导的2型肠炎的新范式，该炎症融合了效果 PGD2和CRTH2，并将告知针对PGD2-CRTH2途径的药物的开发和使用治疗与2型炎症有关的疾病。