Affiliation:
1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research-Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel
2. Institute of Biological Sciences (ISSB-P), UM6P Faculty of Medical Sciences, Mohammed VI Polytechnic University, Ben-Guerir 43150, Morocco
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
−/−
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
−/−
astrocytes compared to
Sema4B
+/-
astrocytes. In vitro experiments indicate that Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, in microglia/macrophage-specific
Plexin-B2
−/−
mice, similar to
Sema4B
−/−
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, 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.
Funder
Israel Science Foundation
Publisher
Proceedings of the National Academy of Sciences