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Astrocyte-to-microglia communication via Sema4B-Plexin-B2 modulates injury-induced reactivity of microglia
Natania Casden1, Vitali Belzer1, Abdellatif El Khayari2
1Department of Developmental Biology and Cancer Research, The Institute for Medical Research-Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
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.
Insights
Astrocytes release Semaphorin4B (Sema4B) that activates microglia/macrophages via Plexin-B2, increasing reactivity after brain injury. Reducing this pathway lessens neuroinflammation and neuronal death, offering therapeutic targets for central nervous system injury.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Central nervous system (CNS) injury triggers rapid cellular responses that can be detrimental to neurons.
- Persistent neuroinflammation following CNS injury increases the risk of neurodegeneration.
- Semaphorin4B (Sema4B), a protein from cortical astrocytes, is implicated in post-injury neuronal death.
Purpose of the Study:
- To investigate the role of Semaphorin4B (Sema4B) in the neuroinflammatory response after cortical injury.
- To identify the receptor for Sema4B on microglia and elucidate the signaling pathway involved.
- To assess the therapeutic potential of targeting the Sema4B-Plexin-B2 pathway in CNS injury.
Main Methods:
- Cortical stab wound injury model in wild-type, Sema4B knockout, and Plexin-B2 knockout mice.
- In vitro co-culture systems of astrocytes and microglia.
- Analysis of cytokine expression, microglial/macrophage reactivity, and neuronal cell death.
Main Results:
- Sema4B knockout mice exhibited attenuated cytokine expression and altered microglial/macrophage reactivity post-injury.
- Sema4B enhanced microglial reactivity in vitro, acting as a ligand for the Plexin-B2 receptor.
- Microglia/macrophage-specific Plexin-B2 knockout mice showed reduced reactivity and neuronal cell death, similar to Sema4B knockout mice.
Conclusions:
- Astrocytic Sema4B acts as a ligand that enhances microglia/macrophage response via Plexin-B2 after CNS injury.
- The Sema4B-Plexin-B2 signaling pathway contributes to neuroinflammation and neuronal death post-injury.
- Targeting this pathway presents a potential therapeutic strategy for mitigating CNS injury consequences.
