The role of GPR84 signaling during skin repair

GPR84 信号在皮肤修复中的作用

• 批准号: 10637039
• 负责人: BRETT SHOOK
• 金额: $ 46.57万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637039
• 关键词: Acute; Adipocytes; Aging; Agonist; Biology; Bone Marrow; Cell Count; Cell physiology; Cells; Cellular biology; Chronic; Communication; Complex; Data; Dermal; Development; Diabetes Mellitus; Disease; Epithelial Cells; Epithelium; Foundations; G-Protein-Coupled Receptors; GPR84 gene; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Genomics; Goals; Growth Factor; Impaired healing; Impaired wound healing; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Learning; Link; Lipids; Lipolysis; LoxP-flanked allele; Macrophage; Medium chain fatty acid; Molecular; Mus; Myelogenous; Myeloid Cells; Pathologic; Patients; Phase; Populations at Risk; Process; Proliferating; Qualifying; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Skin repair; Skin wound healing; Solid; Stromal Cells; System; Testing; Therapeutic; Therapeutic Uses; Tissues; Work; acute wound; aged; antagonist; cell type; cytokine; diabetic; experimental study; genomic tools; healing; immune cell infiltrate; in vitro Assay; in vivo; insight; keratinocyte; migration; mouse model; non-healing wounds; novel; pharmacologic; predictive tools; receptor; recruit; repaired; reparative process; response to injury; single-cell RNA sequencing; small molecule; stem cells; targeted treatment; tissue repair; tool; wound; wound bed; wound healing; wound treatment

ABSTRACT Efficient wound healing requires complex cellular communication between tissue-resident non-immune cells and infiltrating immune cells. While much has been learned about how cytokines and growth factors contribute to acute wound healing, we know very little about how lipid signaling regulates acute inflammation and tissue repair, and identification of new mechanisms that govern acute inflammation and repair is needed. We previously demonstrated that inhibiting dermal adipocyte lipolysis led to reduced macrophage numbers during early inflammation and delayed repair, yet the mechanism(s) linking adipocyte lipolysis to efficient inflammation and repair have not been identified. Given the rising numbers of diabetic and aged patients, it is imperative to define molecular underpinnings that promote a healthy acute inflammatory response and to identify druggable mechanisms to treat inflammation and non- healing wounds. Inhibition of injury-induced dermal adipocyte lipolysis significantly reduces the abundance of medium-chain fatty acids (MCFAs). Recently, GPR84 was identified to be an MCFA receptor that is expressed by bone marrow-derived myeloid cells and during tissue inflammation. Activation of GPR84 in vitro increases macrophage migration and enhances pro-inflammatory gene expression; however, its role in skin and the in vivo mechanism of action is not well defined. We observe increased GPR84-expression during wound-induced inflammation and found that administration of a GPR84 agonist increases macrophage numbers. Additionally, systemic administration of a GPR84 antagonist decreases wound bed macrophages and delays tissue repair. Based on our preliminary data, we hypothesize that GPR84 signaling is required to support macrophage numbers and subsequent repair during injury-induced inflammation. We will combine our team’s tools and expertise in adipocyte, keratinocyte, and macrophage biology with single-cell data interrogation to validate this hypothesis with the following Specific Aims: (1) Use mouse models to determine how GPR84 signaling controls macrophage numbers and subsequent tissue repair after injury, and (2) define how MCFA/GPR84 signaling directly regulates myeloid cell function during skin wound healing and (3) define how epithelial GPR84 signaling contributes to keratinocyte function after injury. GPR84 signaling represents a new window to better understand mechanisms that regulate the injury response. Findings from this proposed work could lay a solid foundation for developing new tools that predict and enhance therapeutic treatment of wound healing.

摘要 有效的伤口愈合需要组织驻留细胞之间复杂的细胞通信， 非免疫细胞和浸润性免疫细胞。虽然已经了解了很多关于如何 细胞因子和生长因子有助于急性伤口愈合，我们知道很少关于如何 脂质信号传导调节急性炎症和组织修复， 需要控制急性炎症和修复的机制。我们先前表明 抑制真皮脂肪细胞脂解导致早期巨噬细胞数量减少， 炎症和延迟修复，但脂肪细胞脂解与有效修复之间的联系机制 炎症和修复尚未确定。鉴于糖尿病患者和老年人的人数不断增加， 患者，必须确定促进健康急性 炎症反应，并确定药物机制，以治疗炎症和非炎症反应。 治愈伤口。 抑制损伤诱导的真皮脂肪细胞脂解显著降低了 中链脂肪酸（MCFA）最近，GPR 84被鉴定为MCFA受体 其由骨髓源性髓样细胞表达并且在组织炎症期间表达。激活 GPR 84在体外增加巨噬细胞迁移并增强促炎基因 然而，其在皮肤中的作用和体内作用机制尚未明确。我们 观察到在伤口诱导的炎症过程中GPR 84表达增加，并发现 GPR 84激动剂的施用增加巨噬细胞数目。此外，系统 施用GPR 84拮抗剂减少了创伤床巨噬细胞并延迟了组织 修复.基于我们的初步数据，我们假设GPR 84信号需要支持 巨噬细胞数量和随后的修复过程中损伤诱导的炎症。我们将 联合收割机将我们团队在脂肪细胞、角质形成细胞和巨噬细胞生物学方面的工具和专业知识与 单细胞数据询问，以验证这一假设与以下具体目的：（1）使用 小鼠模型，以确定GPR 84信号传导如何控制巨噬细胞数量， 损伤后随后的组织修复，以及（2）定义MCFA/GPR 84信号传导如何直接 在皮肤伤口愈合过程中调节骨髓细胞功能和（3）定义上皮GPR 84 信号传导有助于损伤后的角质形成细胞功能。 GPR 84信号转导代表了一个新的窗口，以更好地了解调节 受伤的反应。这项工作的结果可以为开发 预测和增强伤口愈合治疗的新工具。