EXPRESS: HOW TO IMPROVE RECOVERY AFTER INTRACEREBRAL HEMORRHAGE - HEMATOMA CLEARANCE AS A THERAPEUTIC TARGET.

Hemolysis products are very highly cerebrotoxic. However, surgical approaches to evacuate hematoma-containing hemolysis products after intracerebral hemorrhage (ICH) surprisingly showed mixed therapeutic effects. Thus, alternative non-invasive approaches, e.g., those that improve hematoma clearance by endogenous phagocytes, have been experimentally tested and, to date, show highly promising therapeutic benefit for post-ICH recovery. Resident microglia (MG) and monocyte-derived macrophages (together MΦ), important components of the innate immune system, are two highly related professional scavenger cell types that mediate hematoma clearance after ICH. MΦ readily conduct phagocytosis/endocytosis of extravasated blood components, dead/apoptotic cells, and various cellular debris. Unless removed from the brain, these elements induce cytotoxicity and lingering inflammation and form a physical barrier to neuronal re-connectivity, thereby impeding recovery after ICH. Hence, evaluating new therapeutic approaches to improve the efficacy of MΦ-mediated hematoma cleanup could provide a promising strategy to promote post-ICH repair and recovery. The mechanistic bases for these cleanup approaches include: (1) enhancing the expression of scavenger receptors and other phagocytosis-assisting proteins in the MΦ'; (2) blocking the molecules that provide "do not eat me" (anti-phagocytic) signals presenting on the surface of apoptotic cells/debris to be phagocytosed; and (3) protecting the intra-MΦ "health" to sustain effective debris engulfment and degradation, without injuring the phagocytes themselves. We will primarily focus on MΦ-mediated erythrophagocytosis and the detoxification of hemolytic products (hemoglobin, heme, and iron) in the ICH-affected brain. By providing numerous pre-clinical examples, we will demonstrate that the regulation of cleanup is a potential clinically relevant therapeutic target for ICH.