Modulation of Inflammation and Injury by IL-17-Activated Pericytes

 描述（由申请人提供）：炎症是响应微生物感染或有害损伤而产生的一种重要防御机制。这种保护性反应也可能对正常组织功能产生意外的有害后果，包括导致许多现代心血管疾病的病理性组织损伤，如动脉粥样硬化、糖尿病和自身免疫。炎症的经典标志是组织中的白细胞浸润，这是一个协调的过程，涉及细胞间的密切相互作用。 白细胞和血管细胞，即微血管内皮细胞（EC）和周细胞（PC），在毛细血管后微静脉。与EC在传播炎症过程中的良好特征化作用相反，目前关于PC在炎症中的功能的知识基本上缺乏。初步数据表明，白细胞介素（IL）-17，一种与宿主防御和自身免疫有关的促炎细胞因子，激活微血管PC产生许多炎症相关因子。随后的IL-17刺激的PC的RNA测序（RNA-Seq）分析表明，PC合成了许多因子，这些因子对于有效的嗜中性粒细胞介导的宿主防御至关重要。此外，发现刺激的PC是IL-6型细胞因子的活性生产者，包括IL-6、IL- 11和白血病抑制因子（LIF），已知其在各种损伤情况下（包括EC损伤）具有细胞保护作用。在这些RNA-Seq发现的指导下，本研究提出研究PC在IL-17驱动的炎症中的功能。具体而言，研究目标将解决这样的假设，即PC在IL-17介导的炎症中发挥双重作用，即增强中性粒细胞介导的免疫应答，同时最大限度地减少附带的宿主组织损伤。在第一个目标中，本研究将确定PC促进中性粒细胞募集、存活和活化的能力，并表征PC分泌的粒细胞集落刺激因子（G-CSF）在这些过程中的作用。本提案的第二个目的将检查PC赋予的细胞保护作用的情况下，嗜酸性粒细胞介导的损伤的EC。特别地，将评估PC衍生的IL-6型细胞因子对这种保护现象的贡献。成功完成这一建议将扩大最近越来越多的赞赏的作用periendothelial PC作为炎症的积极参与者，这方面的知识是需要全面了解血管系统如何促进免疫反应。从治疗的角度来看，这些发现将揭示重要的IL-17下游通路和靶细胞，并可能导致开发新的治疗方法，改善多种心血管和炎症性疾病的结局。

 DESCRIPTION (provided by applicant): Inflammation is an essential defense mechanism generated in response to microbial infections or injurious insults. This protective response can also have unintended, deleterious consequences on normal tissue functions, including pathological tissue damage leading to many modern cardiovascular diseases, such as atherosclerosis, diabetes, and autoimmunity. A classical hallmark of inflammation is leukocyte infiltration in tissue, a coordinated process that involves intimate cell-cell interactions between leukocytes and vascular cells, namely the microvascular endothelial cells (ECs) and pericytes (PCs), in the postcapillary venules. In contrary to the well-characterized roles of ECs in propagating inflammatory processes, current knowledge regarding the function of PCs in inflammation is essentially lacking. Preliminary data indicate that interleukin (IL)-17, a pro-inflammatory cytokine implicated in host defense and autoimmunity, activates microvascular PCs to produce numerous inflammation-related factors. A subsequent RNA sequencing (RNA-Seq) analysis of IL-17-stimulated PCs demonstrates that PCs synthesize numerous factors essential for effective neutrophil-mediated host defense. Furthermore, stimulated PCs are found to be active producers of IL-6-type cytokines, including IL-6, IL- 11, and leukemia inhibitory factor (LIF), which are known to be cytoprotective in various injurious scenarios, including EC injury. Guided by these RNA-Seq findings, this study proposes to investigate the function of PCs in IL-17-driven inflammation. Specifically, the research aims will address the hypothesis that PCs play dual roles in IL-17-mediated inflammation, namely enhancing neutrophil- mediated immune responses, while minimizing collateral host tissue damage. In the first aim, this study will determine the ability of PCs to promote neutrophil recruitment, survival, and activation, and characterize the role of the PC-secreted granulocyte-colony stimulating factor (G-CSF) in these processes. The second aim of this proposal will examine the PC-conferred cytoprotective effect on ECs in the context of neutrophil-mediated injury. In particular, the contribution of PC-derived IL-6-type cytokines to this protective phenomenon will be assessed. Successful completion of this proposal will expand the recent growingly appreciated roles of periendothelial PCs as active participants in inflammation, and this knowledge is required for the comprehensive understanding of how the vascular system facilitates an immune response. From a therapeutic standpoint, these findings will reveal important IL-17 downstream pathways and target cells, and may lead to development of novel therapies that promise improved outcome for multiple cardiovascular and inflammatory diseases.