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

项目摘要/摘要 慢性移植物抗宿主病(CGVHD)是无复发死亡和 异基因造血干细胞移植后的发病率。其典型的临床表现为 一种自身免疫性综合征和系统性纤维化。最近的研究表明，巨噬细胞与 抗炎的M2表型能够促进cGVHD的纤维化。然而，它在很大程度上仍然 尚未确定是什么驱动了cGVHD部位M2巨噬细胞的极化以及M2巨噬细胞如何 促进GVHD相关的纤维化改变。本应用程序的目标是了解刺猬的角色 (HH)M2巨噬细胞极化和系统性纤维化的信号转导。具体地说，我们将测试 假设HH信号通路是cGVHD靶器官M2巨噬细胞极化的关键， 这反过来又通过产生纤维化因子来促进纤维化。我们将使用老鼠模型和 人类组织追求四个具体目标，这将使我们能够定义HH信号的作用和HH信号的来源 Sonic Hedgehog(SHH)在慢性移植物抗宿主病(CGVHD)促纤维化巨噬细胞中的作用 巨噬细胞介导的导致GVHD持续促纤维化状态的机制和因素，以及 慢性移植物抗宿主病的终末器官纤维化。该项目的长期目标是确定HH信号在 CGVHD对GVHD中巨噬细胞极化影响的机制研究 靶器官及其在免疫细胞失调和组织纤维化中的作用。我们的工作可能会导致 开发治疗慢性移植物抗宿主病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.