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

项目概要/摘要 慢性移植物抗宿主病（cGVHD）是非复发性死亡的主要原因， 异基因造血干细胞移植（HCT）后的发病率。其典型的临床表现为 自身免疫样综合征和系统性纤维化最近的研究表明， 抗炎M2-表型能够促进cGVHD中的纤维化。但在很大程度上， 不确定是什么驱动了M2巨噬细胞在cGVHD部位的极化，以及M2巨噬细胞如何 促进GVHD相关的纤维化变化。这个应用程序的目的是了解刺猬的作用 (Hh)M2巨噬细胞极化和系统性纤维化中的信号传导。具体来说，我们将测试 假设Hh信号通路对于cGVHD靶器官中的M2巨噬细胞极化至关重要， 其又通过产生纤维化因子而促进纤维化。我们将采用小鼠模型， 人类组织追求四个具体的目标，这将使我们能够定义Hh信号的作用和来源， 音刺猬（SHH）促进cGVHD中促纤维化巨噬细胞;我们将描述分子生物学 由巨噬细胞介导的导致GVHD中持续的促纤维化状态的机制和因子，以及 终末器官纤维化本项目的长期目标是确定Hh信号在以下方面的作用： 通过提供其对GVHD内巨噬细胞极化的作用的机制理解， 靶器官及其对免疫细胞失调和组织纤维化的贡献。我们的工作可能会导致 开发用于治疗cGVHD中的系统性纤维化的新治疗策略。

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.