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

 描述(申请人提供)：炎症是对微生物感染或伤害性侮辱做出反应时产生的一种基本防御机制。这种保护性反应也可能对正常组织功能产生意想不到的有害后果，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。炎症的一个典型特征是组织中的白细胞渗透，这是一个协调的过程，涉及细胞与细胞之间的亲密相互作用 毛细血管后小静脉内的白细胞和血管细胞，即微血管内皮细胞(ECs)和周细胞(PC)。与内皮细胞在传播炎症过程中的作用相反，目前关于PC在炎症过程中的作用的知识基本上是缺乏的。初步数据表明，白介素17是一种参与宿主防御和自身免疫的促炎细胞因子，它能激活微血管PC产生许多炎症相关因子。随后对IL-17刺激的PC进行的RNA测序(RNA-Seq)分析表明，PC合成了许多有效的中性粒细胞介导的宿主防御所必需的因子。此外，受刺激的PC被发现是IL-6型细胞因子的活性产生者，包括IL-6、IL-11和白血病抑制因子(LIF)，这些已知在包括EC损伤在内的各种损伤情况下具有细胞保护作用。在这些RNA-Seq发现的指导下，这项研究建议调查PC在IL-17驱动的炎症中的功能。具体地说，这项研究的目的是解决PC在IL-17介导的炎症中扮演双重角色的假设，即增强中性粒细胞介导的免疫反应，同时将伴随的宿主组织损伤降至最低。在第一个目标中，本研究将确定PC促进中性粒细胞募集、存活和激活的能力，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。这项建议的第二个目的将在中性粒细胞介导的损伤的背景下检查PC对内皮细胞的细胞保护作用。特别是，PC来源的IL-6型细胞因子对这种保护现象的贡献将被评估。这一提议的成功完成将扩大最近越来越多的人认识到的内皮周围PC作为炎症的积极参与者的作用，这一知识对于全面了解血管系统如何促进免疫反应是必要的。从治疗的角度来看，这些发现将揭示重要的IL-17下游途径和靶细胞，并可能导致新疗法的开发，有望改善多种心血管和炎症性疾病的结果。

 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.