How to improve recovery after intracerebral hemorrhage: Hematoma clearance as a therapeutic target

Hemolysis products are 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, for example, 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) are two closely 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 preclinical examples, we will demonstrate that the immune modulation of cleanup is a potential clinically relevant therapeutic target for ICH.