Neuron-Derived Sema3B Facilitates Microglial Hematoma Clearance After Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is the deadliest subtype of stroke, and its primary harm to the human body arises from the formation of brain hematomas. Promoting microglial-mediated endogenous hematoma clearance has become a key focus in current ICH treatment strategies. Semaphorin 3s (Sema3s) are molecular signals involved in the regulation of the central nervous system, angiogenesis, and microenvironment homeostasis, and they are closely associated with various central nervous system diseases. Hematoma clearance and inflammation regulation are crucial to the role of microglia, yet the mechanisms by which Sema3s regulate microglia after ICH remain unclear. Here, using high-throughput RNA sequencing of a mouse ICH model, we identified that neuron-derived Sema3B is downregulated after ICH. Further mechanistic studies revealed that Sema3B can bind to PlexinA1 on microglia, activating NRF2 to promote the expression of the phagocytic receptor TREM2 and the key hematoma clearance molecule HO-1. Furthermore, Sema3B enhances the interaction between PlexinA1 and TREM2, cooperatively boosting microglial phagocytosis of the hematoma after ICH. Furthermore, Sema3B regulates the M2 polarization of microglia, exerting an anti-inflammatory effect. Our findings suggest that manipulating microglial phagocytosis of hematoma and inflammation suppression via regulation of Sema3B may be a potential strategy for treating patients with ICH.