Involvement of Sema4D in the control of microglia activation.

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.