Prostaglandin D2 and its receptor CRTH2 regulate intestinal inflammation and homeostasis

前列腺素 D2 及其受体 CRTH2 调节肠道炎症和体内平衡

• 批准号: 10733671
• 负责人: Elia D Tait Wojno
• 金额: $ 47.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733671
• 关键词: Acute; Affect; Agonist; Allergens; Biological; Biology; CCL4 gene; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chronic; Data; Drug Targeting; Environment; Epigenetic Process; Epithelial Cells; Epithelium; Event; Feedback; Food Hypersensitivity; Gene Expression; Goblet Cells; Health; Helminths; Homeostasis; Human; Hyperplasia; Hypersensitivity; Immune; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Interleukin-13; Intestinal Diseases; Intestinal permeability; Intestines; Knockout Mice; LGR5 gene; Laboratories; Lipids; Lung; Malignant Neoplasms; Mediating; Morbidity - disease rate; Mus; Parasites; Pathology; Pathway interactions; Patients; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Population; Positioning Attribute; Prostaglandin D2; Prostaglandins; Recording of previous events; Reporter; Resolution; Role; Shapes; Single Nucleotide Polymorphism; Small Intestines; Stimulus; Testing; Th2 Cells; Work; antagonist; cytokine; epithelial stem cell; fMet-Leu-Phe receptor; gut homeostasis; gut inflammation; helminth infection; in vivo; inhibitor; intestinal barrier; intestinal epithelium; intestinal homeostasis; mast cell; novel; prevent; programs; receptor; receptor expression; repaired; response; stem cell biology; stem cell differentiation; stem cell function; stem cell proliferation

Intestinal epithelial cells (IECs) are central regulators of intestinal homeostasis and organismal well-being. In response to infection or injury, intestinal epithelial stem cells (ISCs) alter their differentiation to promote host-protective inflammation in the epithelium. However, intestinal epithelial inflammation must be tightly regulated to prevent pathology. Type 2 intestinal inflammation occurs during food allergy and parasitic helminth infection that together cause substantial morbidity worldwide. In this context, bioactive lipids are released locally and lipid receptor expression is dynamically regulated, perfectly positioning lipids to fine tune IEC activities. However, how lipids regulate Type 2 epithelial inflammation is poorly defined, representing a gap in our understanding of how intestinal homeostasis is restored following allergy or worm infection. In intestinal Type 2 inflammation, IECs sense stimuli and release alarmins that activate immune cells to secrete the cytokine IL-13, which acts on ISCs to promote their differentiation to secretory goblet and tuft cells. Studies from our laboratory have recently shown that CRTH2, a receptor for the bioactive lipid prostaglandin D2 (PGD2), is expressed in murine and human IECs and enriched in ISCs. CRTH2-deficient ISCs were more likely to differentiate into goblet cells in vitro. PGD2, dependent on CRTH2, counteracted effects of IL-13 on murine small intestine IECs in vitro and in vivo, suppressing goblet cell differentiation during infection with a parasitic helminth. Finally, CRTH2-deficient mice retained goblet cell hyperplasia and increased barrier permeability after the resolution of Type 2 immune activation. Based on these data, we hypothesize that PGD2 acts on CRTH2+ ISCs to return the intestine to homeostasis after a Type 2 inflammatory event and to shape the IEC response to new stimuli. To test this idea, we propose 2 Aims. Aim 1 includes mechanistic studies that will test if PGD2 suppresses ISC differentiation to secretory lineages in response to Type 2 cytokines. Aim 1 will use a novel CRTH2-reporter mouse to identify PGD2-responsive IECs and will test how the PGD2-CRTH2 pathway affects murine and human ISC biology. Aim 2 includes studies that assess the biological significance of PGD2-CRTH2-mediated suppression of IEC responses. Aim 2 will test how PGD2 and CRTH2 affect barrier function and homeostasis and epigenetically program ISCs after Type 2 inflammation and how IEC CRTH2 deficiency during Type 2 inflammation impacts intestinal repair and pathology during a subsequent, acute or chronic inflammatory event. These studies are essential for understanding how PGD2 and CRTH2 aid in restoring gut homeostasis after Type 2 inflammation and will inform the use of existing CRTH2 modulators and other drugs that target lipids in the treatment of intestinal inflammatory disorders.

肠上皮细胞(IECS)是肠道内稳态和机体健康的中心调节者。作为对感染或损伤的反应，肠上皮干细胞(ISCs)改变其分化以促进上皮细胞的宿主保护性炎症。然而，必须严格控制肠道上皮炎症，以防止病理。2型肠道炎症发生在食物过敏和寄生虫感染期间，这两者共同导致全球范围内的大量发病率。在这种情况下，生物活性脂类在局部释放，脂类受体的表达受到动态调节，完美地定位脂类以微调IEC活性。然而，脂质如何调控2型上皮炎症的定义并不明确，这代表着我们对过敏或蠕虫感染后肠道内环境如何恢复平衡的理解存在差距。在肠2型炎症中，IECS感知刺激并释放警报因子，激活免疫细胞分泌细胞因子IL-13，IL-13作用于ISCs，促进其向分泌杯状细胞和簇状细胞分化。最近我们实验室的研究表明，生物活性脂质前列腺素D2(PGD2)的受体CRTH2在小鼠和人的IECs中表达，并在ISCs中丰富。CRTH2缺陷的ISCs在体外更有可能分化为杯状细胞。依赖于CRTH2的PGD2在体外和体内都能拮抗IL-13对小鼠小肠IECs的作用，在感染寄生虫的过程中抑制杯状细胞的分化。最后，CRTH2缺陷小鼠在2型免疫激活解决后保留了杯状细胞的增殖和屏障通透性的增加。根据这些数据，我们假设PGD2作用于CRTH2+ISCs，使肠道在2型炎症事件后恢复内环境平衡，并塑造IEC对新刺激的反应。为了验证这一想法，我们提出了两个目标。目的1包括机制研究，将测试PGD2是否抑制对2型细胞因子反应的ISC向分泌谱系的分化。目的1将使用一种新型的CRTH2报告小鼠来鉴定PGD2反应的IECS，并将测试PGD2-CRTH2途径如何影响小鼠和人类的ISC生物学。目的2包括评估PGD2-CRTH2介导的抑制IEC反应的生物学意义的研究。目的2将测试PGD2和CRTH2如何在II型炎症后影响屏障功能和动态平衡，并对ISCs进行表观编程，以及在随后的急性或慢性炎症事件中，IEC CRTH2缺陷如何影响肠道修复和病理。这些研究对于了解PGD2和CRTH2如何帮助2型炎症后恢复肠道内环境平衡至关重要，并将为使用现有的CRTH2调节剂和其他针对脂质的药物治疗肠炎性疾病提供信息。