Efferocytosis and the resolution of inflammation after intracerebral hemorrhage

项目摘要 脑出血（ICH）是一种破坏性的中风，死亡率为40%， 治疗在ICH的鼠模型中，PI已经证明， 炎性单核细胞向血肿周围区域的转移导致ICH后第一天的显著损伤。 然而，随着时间的推移，这些细胞有助于吞噬作用和功能恢复。调制信号 巨噬细胞从有害到有益是未知的。拟议的工作将确定一个 伤口愈合的基本过程，凋亡细胞的胞浆细胞增多， 大脑和帮助恢复。 初步研究表明，红细胞增多症受体Axl和Mer表达于血液中， 脑出血后脑内巨噬细胞的变化。此外，缺乏Axl和Mer的巨噬细胞具有更高的亲脂性。 在红细胞暴露的情况下，炎症状态和不能响应外源性IL-4。主 一种假说认为，脑出血后Axl和Mer与脑内凋亡细胞的结合， 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途径是否可以减少早期损伤， ICH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.