LAUSR

In Response: We thank Dr Chen et al for their interest in our article. We have demonstrated that CD47 blocking antibody can enhance hematoma clearance through activation of microglia/macrophages and improve functional outcomes in a mouse model of intracerebral hemorrhage (ICH). Their comments raised several important issues, including microglia/macrophage polarization and potential phagocytosis of neurons expressing CD47 if the blocking antibody is given. It is important to understand the role in microglia/macrophage polarization in hematoma removal because hematoma clearance is a therapeutic target in ICH. It should be noted that the effects of microglia/macrophage phenotypes on brain injury/ recovery are complex and controversial. Both M1 and M2 phenotypes have harmful and beneficial effects on brain injury after brain disorders, including ICH. To understand the precise role of microglia/macrophage polarization in brain injury and recovery after ICH, in vivo and in vitro experiments should be performed to evaluate the time course of M1 and M2-polarization after ICH with or without CD47 blocking antibody. We totally agree with Dr Chen et al that using a blocking antibody to target erythrocyte CD47 and enhance hematoma clearance might also have an adverse side effect due to neuronal CD47 expression. We have previously found an increase in perihematomal CD47, including in neurons, after ICH. In the current study, the blocking antibody was given with the hematoma, limiting parenchymal exposure. However, in the cancer field, researchers have examined a bispecific antibody targeting CD47 and epidermal growth factor receptor to more specifically target cancer cells and, in particular, avoid erythrocyte phagocytosis. A similar approach should be possible to help specifically target erythrocyte CD47, that is, a bispecific protein targeting CD47 and another erythrocyte specific membrane protein. We concur with Dr Chen et al that targeting CD47 is an attractive therapeutic strategy for ICH. It might be an adjunct therapy for hematoma evacuation, and we continue to explore the pros and cons of targeting CD47.