Disentangling the Epidermal Immune Crosstalk in Inflammatory Skin Disease

解开炎症性皮肤病中的表皮免疫串扰

• 批准号: 10751902
• 负责人: Alexander Moshensky
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751902
• 关键词: Ablation; Acne; Acute; Adrenal Cortex Hormones; Air; Animal Model; Animals; Atopic Dermatitis; Biology; Blocking Antibodies; Cells; Chemotactic Factors; Collaborations; Data; Development; Disease; Disease Outcome; Disease Progression; Disease model; ERG gene; Embryo; Environmental Hazards; Environmental Risk Factor; Enzymes; Epidermis; Family; Flow Cytometry; Gatekeeping; Genes; Genetic; Glutathione S-Transferase; Homeostasis; Homologous Gene; Hour; Image; Immune; Immune response; Immune system; Immunity; Immunology; Impairment; Inflammation; Inflammatory; Injury; Innate Immune System; Irritants; Knockout Mice; Label; Lasers; Lesion; Leukotriene C4; Leukotriene Production; Leukotrienes; Link; Lipids; Mass Spectrum Analysis; Microsomes; Minor; Mus; Natural Immunity; Neutrophil Infiltration; Pathogenicity; Peptide Hydrolases; Play; Production; Psoriasis; Reactive Oxygen Species; Regulation; Reporting; Research; Retinoids; Role; Running; Site; Skin; Skin injury; Sterility; System; Systems Biology; Transcription Repressor; Zinc Fingers; candidate validation; chemokine; common treatment; extracellular; gene repression; genome wide association study; immunoregulation; improved; inhibitor; injured; interdisciplinary approach; intravital imaging; intravital microscopy; lipid mediator; multidisciplinary; neutrophil; overexpression; pathogen; pharmacologic; prevent; recruit; side effect; single-cell RNA sequencing; skin barrier; skin damage; skin disorder; transcription factor; transcriptome sequencing; wound

Project Summary/ Abstract Inflammatory skin diseases are often multifactorial, with influences from genetics and environmental factors that cause immune dysregulation and impair skin barrier integrity. The epidermis is the outermost layer of the skin and is fundamental to maintaining skin barrier integrity. Also, epidermal skin cells play a primary role in the recruitment and regulation of immune cells upon disruption of homeostasis. The mechanisms that govern the crosstalk between the epidermis and the immune system have yet to be fully elucidated. Current strategies in treating inflammatory skin disease include the administration of corticosteroids and retinoids, which may have unwanted side effects with prolonged use. Therefore, there is a need for a better mechanistic understanding of the crosstalk between the epidermis and the immune system to develop more targeted approaches to treat inflammatory skin disease. Recent reports have implicated SNPs in genes that may play a role in inflammatory skin diseases. One such gene is Ovol1. Ovol1 is a transcriptional repressor of immune cell recruitment and is necessary for maintaining skin homeostasis and regulating proper embryonic epidermis development. Ablation of Ovol1 in psoriasis-like and atopic dermatitis animal models exacerbates disease with an increase of infiltrating neutrophils. Ablation of neutrophils improves disease outcomes. Neutrophils are the principal innate immune responders forming the first line of defense against pathogenic invaders or sterile damages. Neutrophils have an arsenal of effector functions, including the engulfment of pathogens, release of proteases, extracellular trap formation, and release of reactive oxygen species. Appropriately, neutrophils have a destructive potential that requires stringent regulation of recruitment to avoid excess collateral damage to the host. Our preliminary data show that in the absence of epidermal Ovol1, the recruitment of neutrophils to the injured skin increases in minutes. This observation suggests that Ovol1 has a gatekeeping function and prevents the excessive production of neutrophil chemoattractants after skin injury. My central hypothesis is that Ovol1 regulates the production of leukotrienes as well as the expression of chemokines before or minutes after wounding. The absence of epidermal Ovol1 primes the skin for neutrophil infiltration, in turn exacerbating inflammatory skin disease. In this proposal, I will address two aims to support my hypothesis: 1) Evaluate the role of leukotrienes in the excessive recruitment of neutrophils in the absence of epidermal Ovol1, 2) Identify and block chemokines expressed early after skin injury when Ovol1 is absent. The proposed research will untangle the early crosstalk between the epidermis and the innate immune system, potentially revealing better pharmacological targets to alleviate inflammatory skin disease.

项目总结/摘要 炎症性皮肤病通常是多因素的，遗传和环境因素的影响， 导致免疫失调和损害皮肤屏障完整性。表皮是皮肤的最外层 并且是维持皮肤屏障完整性的基础。此外，表皮皮肤细胞在皮肤的生长中起主要作用。 在破坏体内平衡时募集和调节免疫细胞。管理的机制 表皮和免疫系统之间的相互作用尚未完全阐明。目前的战略 治疗炎性皮肤病的方法包括给予皮质类固醇和类维生素A， 长期使用会产生不良副作用。因此，有必要更好地了解 表皮和免疫系统之间的串扰，以开发更有针对性的方法来治疗 炎症性皮肤病。最近的报道暗示基因中的SNP可能在炎症反应中起作用。 皮肤病其中一个基因是Ovol 1。Ovol 1是免疫细胞募集的转录抑制因子， 维持皮肤稳态和调节胚胎表皮正常发育所必需的。消融 银屑病样和特应性皮炎动物模型中Ovol 1的表达会加重疾病， 中性粒细胞中性粒细胞消融可改善疾病结局。 中性粒细胞是主要的先天性免疫应答者，形成抵抗病原性免疫应答的第一道防线。 入侵者或无菌损害。中性粒细胞具有一系列效应子功能，包括吞噬 病原体、蛋白酶释放、细胞外陷阱形成和活性氧物质释放。 适当地，中性粒细胞具有破坏性的潜力，需要严格的招募调节，以避免 对宿主造成额外的附带伤害我们的初步数据表明，在缺乏表皮Ovol 1的情况下， 中性粒细胞向受伤皮肤的募集在几分钟内增加。这一观察表明Ovol 1具有 守门功能，并防止皮肤损伤后中性粒细胞化学引诱物的过度产生。我 中心假设是Ovol 1调节白三烯的产生以及 在受伤前或受伤后几分钟。表皮Ovol 1的缺失使皮肤对中性粒细胞有准备 渗透，反过来加剧炎症性皮肤病。在这个建议中，我将提出两个目标，以支持我的建议。 假设：1）在缺乏中性粒细胞的情况下，评估白三烯在中性粒细胞过度募集中的作用。 表皮Ovol 1，2）当Ovol 1不存在时，鉴定并阻断皮肤损伤后早期表达的趋化因子。的 拟议的研究将解开表皮和先天免疫系统之间的早期串扰， 潜在地揭示了减轻炎症性皮肤病的更好的药理学靶点。