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.

总结 粘膜屏障发育和维持的免疫学控制是一个关键过程，因为粘膜屏障发育和维持的不平衡。 免疫前哨活动可导致皮肤、肺和肠道炎性疾病。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 基于对以下方面的分析，已经确定了涉及组织发育和屏障强化的transcription： 人和小鼠的功能丧失模型。然而，协调3型糖尿病的非炎症因子 在组织中确保适当的免疫反应和防止异常炎症的反应并不好 表征了 我们发现氧化固醇，一种主要的胆固醇代谢物，具有既定的免疫调节作用， 活动，是皮肤中称为Tγδ17细胞的定型3型淋巴细胞的主要位置线索。 Ebi 2（由Gpr 183编码）是G蛋白偶联受体（GPCR），其感测特定类型的氧固醇， 并在所有产生3型细胞因子的淋巴细胞上表达。膳食胆固醇增加可提高Tgd 17 通过增加氧固醇的产生和传感，在皮肤界面处的活性。然而，组织驻留细胞 有助于产生真皮IL-17分泌先天性IL-17的最终位置线索的解剖框架， T淋巴细胞是未知的。此外，氧化固醇是否参与皮肤嗜性Tgd 17的发育， 和其它产生3型细胞因子的淋巴细胞是未知的。 在这个项目中，我们将测试Tgd 17细胞通过感知线索来维持屏障组织稳态的假设 反映营养状态和来自周围神经系统的输入。上皮细胞的代谢变化- 皮肤中的神经元小生境通过GPR 183控制最佳的显微解剖学Tgd 17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早期被印记 胸腺细胞成熟通过与一种新的胸腺上皮细胞亚群的相互作用， 氧化固醇该项目的概念基础是创新的，因为没有氧化固醇的先例- 整合上皮-神经元-免疫通讯的受调节粘膜组织枢纽对屏障组织至关重要 健身