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

Abstract

The inflammatory process in stroke is the major contributor to blood-brain barrier (BBB) breakdown. Previous studies indicated that semaphorin 4D (Sema4D), an axon guidance molecule, initiated inflammatory microglial activation and disrupted endothelial function in the CNS. However, whether Sema4D disrupts BBB integrity after stroke remains unclear. To study the effect of Sema4D on BBB disruption in stroke, rats were subjected to transient middle cerebral artery occlusion and targeted injection of lentivirus-mediated clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene disruption of PlexinB1. We found that Sema4D synchronously increased with BBB permeability and accumulated in the perivascular area after stroke. Suppressing Sema4D/PlexinB1 signaling in the periinfarct cortex significantly decreased BBB permeability as detected by MRI and fibrin deposition, and thereby improved stroke outcome. In vitro, we confirmed that Sema4D disrupted BBB integrity and endothelial tight junctions. Moreover, we found that Sema4D induced pericytes to acquire a CD11b-positive phenotype and express proinflammatory cytokines. In addition, Sema4D inhibited AUF1-induced proinflammatory mRNA decay effect. Taken together, our data provides evidence that Sema4D disrupts BBB integrity and promotes an inflammatory response by binding to PlexinB1 in pericytes after transient middle cerebral artery occlusion. Our study indicates that Sema4D may be a novel therapeutic target for treatment in the acute phase of stroke.-Zhou, Y.-F., Li, Y.-N., Jin, H.-J., Wu, J.-H., He, Q.-W., Wang, X.-X., Lei, H., Hu, B. Sema4D/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats.

Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke

“…Also, activation of the guidance molecule ephrinB2 enhanced neurovascular repair and pericyte recruitment after brain ischemia (47). On the other hand, inhibition of the repulsive axonal guidance molecule Semaphorin 4D reduced BBB permeability as well as infarct volume and improved neurologic performance of rats after transient middle cerebral artery occlusion (48).…”

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis

“…14,15 In addition, anti-SEMA4D antibody suppresses vascular permeability, thereby helping to prevent tumor metastasis or ameliorating symptoms after brain stroke. 16,17 In the field of allergic diseases, previous studies have shown that soluble SEMA4D proteins are present in lung tissue lysates obtained from ovalbumin-treated allergic airway inflammatory models. 18 Furthermore, SEMA4D deficiency affects T-cell activation and ameliorates allergic inflammation in a murine asthma model.…”

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

“…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). Yun Zhang et al indicated that SEMA4D was highly expressed in NK cell line, NK92, and the interaction between SEMA4D and Plexin-B1 played a crucial part in NK cellmediated cytotoxicity against glioma cells (31).…”