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.

项目概要/摘要 炎症性皮肤病通常是多因素的，受到遗传和环境因素的影响 导致免疫失调并损害皮肤屏障的完整性。表皮是皮肤的最外层 对于维持皮肤屏障完整性至关重要。此外，表皮细胞在 体内平衡破坏时免疫细胞的招募和调节。治理机制 表皮和免疫系统之间的串扰尚未完全阐明。目前的策略 治疗炎症性皮肤病包括使用皮质类固醇和类维生素A，这可能有 长期使用会产生不良副作用。因此，需要更好地理解机制 表皮和免疫系统之间的串扰，以开发更有针对性的治疗方法 炎症性皮肤病。最近的报告表明，SNP 与可能在炎症中发挥作用的基因有关 皮肤病。 Ovol1 就是这样的一个基因。 Ovol1 是免疫细胞募集的转录抑制因子， 维持皮肤稳态和调节适当的胚胎表皮发育所必需的。消融 Ovol1 在银屑病样和特应性皮炎动物模型中的表达会随着浸润的增加而加剧疾病 中性粒细胞。中性粒细胞的消融可改善疾病结果。 中性粒细胞是主要的先天免疫应答者，形成抵御病原体的第一道防线 入侵者或无菌损害。中性粒细胞具有一系列效应功能，包括吞噬 病原体、蛋白酶的释放、细胞外陷阱的形成以及活性氧的释放。 适当地，中性粒细胞具有破坏性潜力，需要严格调节招募以避免 对宿主造成过多的附带损害。我们的初步数据表明，在表皮 Ovol1 缺失的情况下， 受伤皮肤的中性粒细胞募集会在几分钟内增加。这一观察结果表明 Ovol1 具有 守门功能并防止皮肤损伤后中性粒细胞趋化剂的过量产生。我的 中心假设是 Ovol1 调节白三烯的产生以及 受伤前或受伤后几分钟内的趋化因子。表皮 Ovol1 的缺失使皮肤为中性粒细胞做好准备 渗透，进而加剧炎症性皮肤病。在这个提案中，我将提出两个目标来支持我的 假设：1）评估白三烯在缺乏中性粒细胞过度募集中的作用 表皮 Ovol1, 2) 当 Ovol1 缺失时，识别并阻断皮肤损伤后早期表达的趋化因子。这 拟议的研究将解开表皮和先天免疫系统之间的早期串扰， 可能揭示减轻炎症性皮肤病的更好的药理学靶点。