S1P2 contributes to microglial activation and M1 polarization following cerebral ischemia through ERK1/2 and JNK

Abstract

Sphingosine 1-phosphate (S1P) signaling has emerged as a drug target in cerebral ischemia. Among S1P receptors, S1P 2 was recently identified to mediate ischemic brain injury. But, pathogenic mechanisms are not fully identified, particularly in view of microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed whether microglial activation is the pathogenesis of S1P 2 -mediated brain injury in mice challenged with transient middle cerebral artery occlusion (tMCAO). To suppress S1P 2 activity, its specific antagonist, JTE013 was given orally to mice immediately after reperfusion. JTE013 administration reduced the number of activated microglia and reversed their morphology from amoeboid to ramified microglia in post-ischemic brain after tMCAO challenge, along with attenuated microglial proliferation. Moreover, JTE013 administration attenuated M1 polarization in post-ischemic brain. This S1P 2 -directed M1 polarization appeared to occur in activated microglia, which was evidenced upon JTE013 exposure in vivo as suppressed M1-relevant NF-κB activation in activated microglia of post-ischemic brain. Moreover, JTE013 exposure or S1P 2 knockdown reduced expression levels of M1 markers in vitro in lipopolysaccharide-driven M1 microglia. Additionally, suppressing S1P 2 activity attenuated activation of M1-relevant ERK1/2 and JNK in post-ischemic brain or lipopolysaccharide-driven M1 microglia. Overall, our study demonstrated that S1P 2 regulated microglial activation and M1 polarization in post-ischemic brain.

A Sphingosine 1-Phosphate Gradient Is Linked to the Cerebral Recruitment of T Helper and Regulatory T Helper Cells during Acute Ischemic Stroke

“…It has been shown that the S1P 2 is more abundantly expressed on vascular endothelial cells after cerebral ischemia [ 17 ], involved in vascular permeability and inflammation [ 59 , 60 ] with potential influence on lymphocyte traffic to and within the brain [ 61 ]. Moreover, S1P 2 was recently linked to a pro-inflammatory response by inducing M1 polarization after cerebral ischemia [ 62 ]. In contrast, S1P 3 is expressed in embryonic endothelial cells and is required for endothelial cell morphogenesis as well as migration [ 63 , 64 , 65 ].…”

The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain

“…In cerebral ischemia, S1P2 mediates ischemic brain injury [132]. Inhibition of S1P2 resulted in the restoration of the ramified morphology of microglia, reduced proliferation and reduction of the M1 marker NF-κB, suggestively by reducing phosphorylation levels of ERK1/2 and JNK, but not Akt and p38 MAPK [133].…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…Microglia activation by lipopolysaccharide stimulation is associated with downregulation of S1PR1 and without any change in S1PR2 and S1PR3 [104]. Recent data indicate that S1PR1-3 are associated with M1 microglial polarization in the ischemic brain by regulating ERK1/2, JNK, p38 MAPKs, and Akt [105][106][107]. S1PR5 is preferentially expressed in oligodendrocytes [108].…”