Functional diversity of lung pericytes in lung injury

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ABSTRACT Pericytes have been implicated in lung injury and repair in a number of organs. Our research focuses on the role of lung stromal subpopulations in tissue injury and repair, and our recent work revealed lung pericytes may have multiple functional roles during injury. Data from transcriptomic analyses of activated lung pericytes reveal upregulation of multiple genes involved in inflammation, angiogenesis, and matrix remodeling. The goal of this project is to characterize the functional diversity of pericytes in their response to a clinically relevant model of lung injury – influenza infection. To achieve this goal, we will test hypotheses on the roles of pericytes in endothelial and immune regulation. In Aim 1, we will investigate the mechanisms of pericyte-endothelial cell crosstalk that lead to activation of endothelial cells and increased lung permeability. Angiopoietin-L4 (ANGPTL4) has been implicated as a hyperpermeability factor that is also highly upregulated in activated lung pericytes in our preliminary studies. We will examine how pericyte- derived ANGPTL4 affects lung endothelial function in this aim. In Aim 2, we will evaluate the role of lung pericytes in trafficking inflammatory monocytes. In murine models of influenza infection, inflammatory monocytes have been implicated in the development of lung injury. Recruitment of inflammatory monocytes in influenza occurs through a CC-chemokine receptor 2 (CCR2) dependent mechanism. Our work shows that activated pericytes highly upregulate CCL2, a major ligand for CCR2. We will evaluate the functional role of pericyte-derived CCL2, and other CCR2 ligands, in inflammatory monocyte recruitment. Finally, in Aim 3, we will characterize functional subsets in the pericyte population using single nucleus transcriptomic approaches. This proposed aim will provide insight into the diverse functional states of lung pericytes throughout the course of influenza infection and functional subtypes that mediate lung injury.