Efferocytosis and the resolution of inflammation after intracerebral hemorrhage

项目摘要 脑出血(ICH)是一种破坏性的卒中类型，40%的病死率和 治疗。在脑出血的小鼠模型中，PI已经证明了血液来源的募集 在脑出血后的头几天，血肿周围的炎性单核细胞会导致严重的损伤。 然而，随着时间的推移，这些细胞有助于吞噬和功能恢复。调制的信号 巨噬细胞从有害到有益，目前尚不清楚。拟议的工作将决定一个 伤口愈合的基本过程，即凋亡细胞的胞吐作用，在消除伤口炎症中的作用 大脑和帮助恢复。 初步研究表明，泡腾细胞吞噬受体Axl和Mer在血液中有表达。 脑出血后脑内衍生的巨噬细胞。此外，缺乏Axl和Mer的巨噬细胞具有更高的促凝活性。 在红血球暴露的情况下，炎症状态和对外源IL-4的反应失败。初级阶段 假说是脑出血后脑内细胞凋亡导致Axl和Mer的结合 巨噬细胞向有助于伤口愈合和脑修复的表型极化。总目标 该提案的目的是确定操纵这一通路是否可以减少早期损伤并增强 脑出血后修复。

Project Summary Intracerebral hemorrhage (ICH) is a devastating type of stroke with 40% fatality and no specific treatment. In a murine model of ICH, the PI has demonstrated that the recruitment of blood-derived inflammatory monocytes to the perihematomal region leads to significant injury in the first days after ICH. However, over time, these cells contribute to phagocytosis and functional recovery. The signals that modulate the macrophages from injurious to beneficial are unknown. The proposed work will determine the role of a fundamental process in wound healing, the efferocytosis of apoptotic cells, in resolving inflammation in the brain and aiding in recovery. Preliminary work demonstrates that the efferocytosis receptors Axl and Mer are expressed on blood- derived macrophages in the brain after ICH. Furthermore, macrophages lacking Axl and Mer have higher pro- inflammatory states and fail to respond to exogenous IL-4 in the context of erythrocyte exposure. The primary hypothesis is that the engagement of Axl and Mer by apoptotic cells in the brain after ICH drives the polarization of macrophages towards phenotypes that aid in wound healing and brain repair. The overall goal of the proposal is to determine whether manipulation of this pathway can reduce early injury and enhance repair after ICH.