Astrocyte-to-microglia communication via Sema4B-Plexin-B2 modulates injury-induced reactivity of microglia

Abstract After central nervous system injury, a rapid cellular and molecular response is induced. This response can be both beneficial and detrimental to neuronal survival in the first few days and increases the risk for neurodegeneration if persistent. Semaphorin4B (Sema4B), a transmembrane protein primarily expressed by cortical astrocytes, has been shown to play a role in neuronal cell death following injury. Our study shows that after cortical stab wound injury, cytokine expression is attenuated in Sema4B knockout mice and microglia/macrophage reactivity is altered. In vitro , Sema4B enhances the reactivity of microglia following injury, suggesting astrocytic Sema4B functions as a ligand. Moreover, injury-induced microglia reactivity is attenuated in the presence of Sema4B knockout astrocytes compared to heterozygous astrocytes. In vitro , experiments indicate Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, in microglia/macrophage-specific Plexin-B2 knockout mice, similar to Sema4B knockout mice, microglial/macrophage reactivity and neuronal cell death are attenuated after cortical injury. Finally, in Sema4B/Plexin-B2 double heterozygous mice, microglial/macrophage reactivity is also reduced after injury, thus supporting the idea that both Sema4B and Plexin-B2 are part of the same signaling pathway. Taken together, we propose a model in which following injury, astrocytic Sema4B enhances the response of microglia/macrophages via Plexin-B2, leading to increased reactivity. Significance statement In this study, we show that in the brain cortex, Sema4B, a protein mainly expressed by astrocytes, plays a crucial role in enhancing the reactivity of microglia/macrophages via Plexin-B2. These findings reveal new molecular signaling instigated by astrocytes toward microglia/macrophages in the context of central nervous system (CNS) injury, shedding new light on the complex interplay between astrocytes and microglia/macrophages. Taken together, our findings suggest that targeting the Sema4B/Plexin-B2 pathway could be a promising therapeutic approach for reducing microglia reactivity and improving the adaptive response in the context of CNS injury.