Cholesterol metabolites coordinate skin barrier immunity centered on innate dermal gammadelta T cells programmed to produce IL-17

胆固醇代谢物协调以先天真皮 γδ T 细胞为中心的皮肤屏障免疫，这些细胞被编程为产生 IL-17

• 批准号: 10366952
• 负责人: Joonsoo Kang
• 金额: $ 70.36万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366952
• 关键词: 25-hydroxycholesterol; Acute; Anatomy; Arthritis; Atopic Dermatitis; Autoimmune Diseases; Binding Proteins; Biochemical; Birth; Cell Communication; Cell Maintenance; Cell physiology; Cells; Cholesterol; Cholesterol Homeostasis; Communication; Cues; Cutaneous; Cytokine Receptors; Data; Dermal; Dermis; Development; Diet; Diet Modification; Dietary Cholesterol; Dietary Fats; Disease; Eczema; Ensure; Enzymes; Epidermis; Epithelial; Epithelial Cells; Fatty acid glycerol esters; Food; Funding; G-Protein-Coupled Receptors; Generations; Genetic Transcription; High Fat Diet; Homeostasis; Homing; Human; Hyperactivity; Immune; Immunity; Immunologics; Impairment; Incidence; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intake; Interleukin-17; Intervention; Knowledge; Lead; Ligands; Link; Lung; Lymphocyte; Lymphoid Cell; Maintenance; Maps; Mediating; Metabolic; Metabolic Diseases; Mixed Function Oxygenases; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Neuroglia; Neurons; Nociceptors; Nutritional; Obesity; Pain; Pathway interactions; Pattern; Peripheral Nerves; Positioning Attribute; Pregnancy; Process; Production; Psoriasis; Regulation; Reporter; Response Elements; Rest; SOX4 gene; Schwann Cells; Sentinel; Severities; Shapes; Skin; Specific qualifier value; Specificity; Sterols; Stromal Cells; System; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; base; cell type; chronic inflammatory skin; commensal bacteria; cytokine; dietary; fitness; fortification; immunoreaction; immunoregulation; imprint; innovation; insight; interleukin-22; keratinocyte; loss of function; mouse model; non-genetic; novel; oxysterol 7-alpha-hydroxylase; pathogen; prevent; response; sensor; sensory mechanism; skin barrier; skin disorder; skin organogenesis; thymocyte; trait; transcription factor; western diet

Summary Immunological control of mucosal barrier development and maintenance is a critical process, as imbalances in immune sentinel activity can lead to skin, lung and gut inflammatory diseases. Central in the mucosal tissue homeostasis are type 3 cytokine producing lymphocytes. Cytokines, cytokines receptors and master transcriptions involved in tissue development and barrier fortification have been identified based on analyses of loss of function models in human and mice. However, non-inflammatory factors that orchestrate the type 3 responses in tissues to assure proper immune reactions and prevent aberrant inflammation have not been well characterized. We discovered that oxysterols, a major class of cholesterol metabolites with established immunomodulatory activities, are the primary positional cues for the stereotypical type 3 lymphocytes in the skin called Tγδ17 cells. Ebi2 (encoded by Gpr183) is the G protein coupled receptor (GPCR) that senses specific types of oxysterols, and is expressed on all type 3 cytokine producing lymphocytes. Increased dietary cholesterol enhances Tgd17 activity at the skin interface via augmented oxysterol production and sensing. However, how tissue resident cells contribute to the anatomical framework that generate the final positional cues for dermal IL-17 secreting innate T lymphocytes is not known. Moreover, whether oxysterols are involved in the development of skin-tropic Tgd17 and other type 3 cytokine producing lymphocytes is not known. In this project we will test the hypothesis that Tgd17 cells maintain barrier tissue homeostasis by sensing cues that reflect nutritional states and inputs from the peripheral nerve system. Metabolic changes in the epithelial- neuronal niche in the skin control optimal microanatomical Tgd17 positioning and function via GPR183. This integrated sensory mechanism for cholesterol metabolism and neuronal inputs is imprinted early in Tγδ17 thymocyte maturation through interactions with a novel subset of thymic epithelial cells programmed to produce oxysterols. The conceptual basis of this project is innovative as there are no precedents for the oxysterol- regulated mucosal tissue hub integrating epithelial-neuronal-immune communications critical for barrier tissue fitness.

概括 粘膜屏障发育和维持的免疫控制是一个关键过程，因为粘膜屏障的不平衡 免疫前哨活动可导致皮肤、肺部和肠道炎症性疾病。位于粘膜组织中央 体内平衡是产生 3 型细胞因子的淋巴细胞。细胞因子、细胞因子受体和主控 根据以下分析，已确定参与组织发育和屏障强化的转录 人类和小鼠的功能丧失模型。然而，协调 3 型炎症反应的非炎症因子 确保适当免疫反应和防止异常炎症的组织反应尚未良好 特点。 我们发现氧甾醇是一类主要的胆固醇代谢物，具有已确定的免疫调节作用 活动，是皮肤中称为 Tγδ17 细胞的典型 3 型淋巴细胞的主要位置线索。 Ebi2（由 Gpr183 编码）是 G 蛋白偶联受体 (GPCR)，可感知特定类型的氧甾醇， 并在所有产生 3 型细胞因子的淋巴细胞上表达。膳食胆固醇增加可增强 Tgd17 通过增强氧甾醇的产生和传感来增强皮肤界面的活性。然而，组织驻留细胞如何 有助于形成解剖框架，为真皮分泌先天性 IL-17 生成最终位置线索 T 淋巴细胞尚不清楚。此外，氧甾醇是否参与亲肤性Tgd17的发展 而其他产生 3 型细胞因子的淋巴细胞尚不清楚。 在这个项目中，我们将测试 Tgd17 细胞通过感知信号维持屏障组织稳态的假设 反映营养状态和周围神经系统的输入。上皮细胞的代谢变化 皮肤中的神经元生态位通过 GPR183 控制最佳的微解剖学 Tgd17 定位和功能。这 胆固醇代谢和神经元输入的综合感觉机制在 Tγδ17 的早期就已被印记 胸腺细胞通过与胸腺上皮细胞的新亚群相互作用而成熟，该细胞被编程为产生 氧甾醇。该项目的概念基础是创新的，因为氧甾醇没有先例。 调节粘膜组织中枢，整合对屏障组织至关重要的上皮-神经元-免疫通讯 健康。