Effect of Sema4D on microglial function in middle cerebral artery occlusion mice

Abstract

Cerebral ischemia evokes neuroinflammatory response. Inflammatory stimulation induces microglial activation, such as changes of their morphology from ramified to ameboid, expression of iNOS and cytokines, and the elevation of proliferative activity. Activated microglia play important roles in pathogenesis of cerebral ischemia. A previous study indicated that Sema4D promoted iNOS expression in cultured microglia; however, roles of Sema4D on microglial activation in ischemic injury remains unclear. We investigated the effect of Sema4D-deficiency on microglial activation by using permanent middle cerebral artery occlusion (MCAO) in mice. In this study, ischemia-induced activated microglia were classified into activated-ramified microglia and ameboid microglia based on their morphology. We demonstrated that the rate of iNOS expression in activated-ramified microglia was lower than that in ameboid microglia, while the most proliferating microglia were activated-ramified microglia but not ameboid microglia after cerebral ischemia. Sema4D-deficiency decreased the number of ameboid microglia and iNOS-expressing activated-ramified microglia in the peri-ischemic cortex. These changes by Sema4D-deficiency contributed to the reduction of NO production that was estimated by nitrite concentration in ischemic cortex. On the other hand, Sema4D-deficiency promoted proliferation of microglia in the peri-ischemic cortex. Importantly, ischemia-induced apoptosis and postischemic behavioral abnormality were moderated in Sema4D(-/-) mice. These findings suggest that Sema4D promotes cytotoxic activation of microglia and inhibits functional recovery after cerebral ischemia.

Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization

“…In addition to the increase in the population, S1P 3 in the ischemic brain was closely associated with the morphological transformation of activated microglia. In the ischemic core regions 3 days or more after ischemic challenge, most of the activated microglia were amoeboid shaped and were mainly responsible for neuronal damage in ischemic brain by releasing several proinflammatory mediators [ 49 , 50 ]. We demonstrated that inhibiting S1P 3 resulted in a significant attenuation of the transformation of activated microglia into an amoeboid shape.…”

A competing endogenous RNA mechanism in glioblastoma is investigated by bioinformatics analysis

“…Studies by John R. Basile et al revealed that the size and vascular distribution of head and neck squamous cell carcinomas (HNSCC) tumor xenografts could be significantly reduced after SEMA4D knockdown (28). Besides, SEMA4D also promoted the cytotoxic activation of microglia and suppressed functional recovery after cerebral ischemia (29). Moreover, SEMA4D damaged the integrity of bloodbrain barrier and promoted inflammatory response by binding to PlexinB1 after transient middle cerebral artery occlusion (30).…”

Sema4D/PlexinB1 inhibition ameliorates blood‐brain barrier damage and improves outcome after stroke in rats

“…Previous studies demonstrated that Sema4D is responsible for axon growth and angiogenesis, resulting in neural development and tumor growth (55, 59). However, recent studies suggest that Sema4D/PlexinB1 signaling plays a crucial role in the inflammatory and immune response under hypoxia (60, 61). Okuno et al (17) demonstrated that Sema4D/PlexinB1 signaling significantly promoted neuroinflammation during experimental autoimmune encephalomyelitis development.…”

“…Okuno et al (17) demonstrated that Sema4D/PlexinB1 signaling significantly promoted neuroinflammation during experimental autoimmune encephalomyelitis development. Using Sema4D ‐/‐ mice, Sawano et al (61) indicated that Sema4D deficiency inhibited the inflammatory response after ischemic injury via the reduction of iNOS‐expressing activated‐ramified microglia. In this study, we found that both Sema4D‐positive cells and CD11b‐high pericytes presented in the periinfarct area, and part of Sema4D expression collocated with CD11b‐high pericytes in the perivascular area at d 1 and 3 after tMCAO.…”