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

Yale University, New Haven CT

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Abstract

? 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.