Involvement of Sema4D in the control of microglia activation
Marcia Toguchi1, Daniel Gonzalez, Sohei Furukawa
1Osaka University, Yamadaoka, Suita-shi, Japan.
Abstract:
Microglia normally exist in a resting state characterized by a ramified morphology, and are responsible for immune surveillance in the CNS. However, the resting microglia rapidly transform towards an activated phenotype in response to brain injury or immunological stimuli. In certain pathological conditions, the unregulated response or over-activation of microglia can provoke severe neuronal damage. Here, we have investigated whether Semaphorin4D (Sema4D/CD100) could function as a potential factor to control activation. Microglia were cultured, activated by bacterial endotoxin lipopolysaccharide (LPS) and then, exposed to Sema4D/CD100 or conditioned medium. We found that Sema4D/CD100 negatively controlled LPS-induced morphological activation. Moreover, intracerebral injection of LPS-induced abundant microglial activated forms in mice lacking Sema4D/CD100. Sema4D/CD100 also inhibited other relevant aspects of cell activation. Treatment with Sema4D/CD100 inhibited the production of nitrites and LPS-induced microglia migration. We also provide evidence that LPS markedly upregulated Plexin-B1 expression in microglia and Sema4D/CD100 stimulated RhoA-activation in LPS-activated microglia. Taken together, these findings suggest a novel role of Sema4D/CD100 in the regulation of microglia activation providing a valuable neuroprotective tool to the CNS.
Insights
Semaphorin4D (Sema4D/CD100) regulates microglial activation, a key immune cell in the central nervous system. This study shows Sema4D/CD100 acts as a neuroprotective factor by inhibiting harmful microglial responses.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are crucial for central nervous system (CNS) immune surveillance but can cause neuronal damage when over-activated.
- Uncontrolled microglial activation is implicated in various neuropathologies.
Purpose of the Study:
- To investigate the role of Semaphorin4D (Sema4D/CD100) in regulating microglial activation.
- To determine if Sema4D/CD100 possesses neuroprotective properties by modulating microglial responses.
Main Methods:
- Primary microglia cultures were activated with lipopolysaccharide (LPS).
- Cells were treated with Sema4D/CD100 or conditioned medium.
- Intracerebral LPS injections were performed in mice lacking Sema4D/CD100.
- Microglial morphology, nitrite production, migration, and RhoA activation were assessed.
Main Results:
- Sema4D/CD100 significantly inhibited LPS-induced microglial morphological activation and migration.
- Mice lacking Sema4D/CD100 exhibited increased microglial activation following intracerebral LPS injection.
- Sema4D/CD100 treatment reduced nitrite production and modulated RhoA activation in LPS-activated microglia.
- LPS upregulated Plexin-B1 expression in microglia, suggesting a potential interaction pathway.
Conclusions:
- Semaphorin4D/CD100 plays a novel inhibitory role in the regulation of microglial activation.
- Sema4D/CD100 demonstrates potential as a neuroprotective agent for the CNS.
- Targeting Sema4D/CD100 may offer therapeutic strategies for neuropathological conditions involving microglial over-activation.
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