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.
Intracerebral hemorrhage (ICH) is a devastating type of stroke with 40% fatality and no specific treatment. The overall goal of the proposal is to determine the mechanisms by which macrophages contribute to recovery with the goal of identifying a new treatment target to improve outcomes for patients with ICH.
|Murphy, Meredith P; Kuramatsu, Joji B; Leasure, Audrey et al. (2018) Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage. Stroke 49:2652-2658|
|Chang, Che-Feng; Goods, Brittany A; Askenase, Michael H et al. (2018) Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest 128:607-624|