Role of macrophage polarization in multi-organ fibrosis of chronic GVHD

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Project Summary/Abstract Chronic graft versus host disease (cGVHD) represents the leading cause of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (HCT). It is typically clinically manifested as an autoimmune-like syndrome and systemic fibrosis. Recent studies have suggested that macrophages with an anti-inflammatory M2-phenotype are capable of promoting fibrosis in cGVHD. However, it remains largely undefined what drives the polarization of M2 macrophages at sites of cGVHD and how M2 macrophages promote GVHD-related fibrotic changes. The objective of this application is to understand the role of hedgehog (Hh) signaling in the polarization of M2 macrophages and systemic fibrosis. Specifically, we will test the hypothesis that the Hh signaling pathway is critical for M2 macrophage polarization in cGVHD target organs, which in turn promotes fibrosis through the production of fibrogenic factors. We will employ mouse models and human tissues to pursue four specific aims that will allow us to define the role of Hh signaling and the source of sonic hedgehog (SHH) in promoting pro-fibrotic macrophages in cGVHD; we will delineate molecular mechanisms and factors mediated by macrophages that lead to an ongoing pro-fibrotic state in GVHD, and end-organ fibrosis in cGVHD. The long-term objective of this project is to define the role of Hh signaling in cGVHD by providing a mechanistic understanding of its effects on macrophage polarization within GVHD target organs and its contributions to immune cell dysregulations and tissue fibrosis. Our work may lead to the development of novel therapeutic strategies for treating systemic fibrosis in cGVHD.