Inflammatory Cytokines Promotes Pro-Fibrotic Thy-1 Negative Fibroblast Subpopulations In Lung Fibrosis

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Idiopathic pulmonary fibrosis (IPF) is a fatal disease with no clear pathogenesis or cure. It is characterized by chronic inflammatory cell infiltration, elevated inflammatory cytokines, myofibroblast accumulation, and aberrant extracellular matrix (ECM) remodeling. Fibroblastic foci, the regions of active fibrogenesis in the lung, are characterized by fibroblasts lacking the critical integrin adaptor protein, Thy-1. The loss of Thy-1 leads to aberrant mechanotransduction, myofibroblastic differentiation, and matrix remodeling. These changes are sufficient to recruit Thy-1 positive naïve fibroblasts into the fibrotic program and drive non-resolving fibrosis. The mechanism of Thy-1 loss in fibroblasts is not known. Separately, others have implicated inflammatory cytokines in the pathogenesis of pulmonary fibrosis without understanding how chronic inflammation leads to disrupted mechanotransduction and altered tissue mechanics driving disease progression. The objective of this application is to investigate the connections between inflammation and disrupted mechanotransduction characteristic of disease progression. I propose the central hypothesis that a novel IL-1-Thy-1 axis exists whereby IL-1 promotes acute Thy-1 loss in naïve fibroblasts and leads to a secondary wave of inflammation characterized by TNF-α production that results in chronic loss of Thy-1. We propose to identify the consequences of IL-1β- and TNF-α-mediated Thy-1 loss in lung fibroblasts by investigating myofibroblast differentiation and changes in mechanotransduction. Additionally, I will determine the mechanism of Thy-1 by looking at changes in vesicular shedding and epigenetic silencing using imaging flow cytometry and ATAC- Seq, respectively (Aim 1). Last, I propose to determine the localization and functional role of IL-1 and TNF-α in pulmonary fibrosis by using spatially targeted optical microproteomics and mouse models (Aim 2). This proposed work is significant in that it would fill a substantial gap in our knowledge by establishing a mechanism by which inflammation contributes to the onset and persistence of IPF through the establishment of stable fibroblast subpopulations. We pose an innovative hypothesis that seeks, for the first time, to bridge the gap between inflammation and disrupted mechanotransduction characteristic of disease progression.