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（IEC）是肠道稳态和生物体健康的中心调节因子。肠上皮干细胞（ISCs）对感染或损伤的反应是改变其分化，以促进上皮中的宿主保护性炎症。然而，必须严格调节肠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，它们共同导致世界范围内的大量发病率。在这种情况下，生物活性脂质局部释放，脂质受体表达动态调节，完美定位脂质微调IEC活动。然而，脂质如何调节2型上皮炎症的定义很差，这代表了我们对过敏或蠕虫感染后肠道内稳态如何恢复的理解存在差距。在肠道2型炎症中，IEC感知刺激并释放alarmin，其激活免疫细胞以分泌细胞因子IL-13，其作用于ISC以促进其分化为分泌性杯状细胞和簇状细胞。我们实验室的研究最近表明，CRTH 2，一种生物活性脂质前列腺素D2（PGD 2）的受体，在小鼠和人IEC中表达，并在ISC中富集。CRTH 2缺陷的ISCs更可能在体外分化为杯状细胞。PGD 2依赖于CRTH 2，在体外和体内抵消IL-13对小鼠小肠IEC的作用，在寄生蠕虫感染期间抑制杯状细胞分化。最后，CRTH 2缺陷型小鼠在2型免疫激活消退后保留杯状细胞增生并增加屏障通透性。基于这些数据，我们假设PGD 2作用于CRTH 2 + ISCs，使肠在2型炎症事件后恢复稳态，并塑造IEC对新刺激的反应。为了验证这个想法，我们提出了两个目标。目的1包括将测试PGD 2是否抑制ISC响应于2型细胞因子分化为分泌谱系的机制研究。目的1将使用一种新的CRTH 2报告小鼠来鉴定PGD 2反应性IEC，并将测试PGD 2-CRTH 2通路如何影响小鼠和人ISC生物学。目的2包括评估PGD 2-CRTH 2介导的IEC反应抑制的生物学意义的研究。目的2将测试PGD 2和CRTH 2如何影响屏障功能和稳态，以及2型炎症后表观遗传学程序ISC，以及2型炎症期间IEC CRTH 2缺陷如何影响随后急性或慢性炎症事件期间的肠道修复和病理学。这些研究对于了解PGD 2和CRTH 2如何帮助恢复2型炎症后的肠道稳态至关重要，并将为使用现有的CRTH 2调节剂和其他靶向脂质的药物治疗肠道炎症性疾病提供信息。