Abstract
Sphingosine 1-phosphate (S1P) is involved in a variety of cellular responses including microglial activation and polarization. However, the impacts of S1P on ischemia-induced microglial activation and polarization remain unclear. In the present study, Sprague-Dawley rats were selected for middle cerebral artery occlusion (MCAO) establishment and treated with S1P analog FTY720 (0.5, 1, 2 mg/kg) for 24 h. The impacts of FTY720 on oxygen-glucose deprivation (OGD)-induced microglial polarization were examined in the primary cultured microglia. FTY720 treatment could prevent ischemia-induced brain injury and neurological dysfunction, also decrease the levels of IL-1β and TNF-α and promote M2 microglial polarization in rats. Further, we found that FTY720 inhibited the expressions of M1 markers, but increased the expressions of M2 markers in the OGD-insulted microglia. And FTY720 could enhance the phagocytic function of microglia. The sphingosine kinase 1/2 (SphK1/2) or the Sphk2 inhibitor could prevent the M1 to M2 phenotype shift improved by FTY720, but the Sphk1 inhibitor failed to affect the roles of FTY720. Furthermore, the Sphk1/2 or Sphk2 inhibitor promoted the activities of histone deacetylase (HDAC1) and inhibited the histone acetylation of the Krüppel-like factor 4 (KLF4) promoter regions, indicating that intra-nuclear pFTY720 inhibited HDAC1 activations and prevented KLF4 to interact with HDAC1, and thereby suppresses KLF4 deacetylation. Therefore, our data reveals that intra-nuclear SphK2-S1P axis might facilitate the transformation of microglial polarization from M1 to M2 phenotype, which might be intra-nuclear regulatory mechanisms of FTY720-prevented neuroinflammation.
Highlights
Ischemia stroke is recognized as a leading cause of morbidity, mortality, and disability among adults around the world [1], which occurs as a result of interrupted blood supply to the brain parenchyma
To evaluate the effect of FTY720 (Figure 1A shows the schematic structure of FTY720) in stroke-induced brain injury, the neurological deficit score and the infarct volume were analyzed at 24 h after ischemic/reperfusion
Rats treated with 2 mg/kg FTY720 showed a significant reduction in cerebral infarct volume by ≈40% compared with middle cerebral artery occlusion (MCAO) group (Figures 1D,E)
Summary
Ischemia stroke is recognized as a leading cause of morbidity, mortality, and disability among adults around the world [1], which occurs as a result of interrupted blood supply to the brain parenchyma. Sphk2-S1P Facilitates Microglial M1-to-M2 Shift appreciated that ischemic stroke rapidly activates the immune inflammatory response in the brain [2, 3], which subsequently aggravates the ischemic cascade mediated neuronal cell death and ischemia/reperfusion (I/R) injury. Recent researches indicate that anti-inflammation is an important therapeutic strategy for stroke. It is well-known that microglia is the prime resident innateimmune cell, which is rapidly activated and causes secondary injury by releasing inflammatory cytokines when cerebral ischemia occurred [4, 5]. Alternatively activated microglia can protect neighboring cells and promote tissue repair by removing cell debris and releasing anti-inflammatory cytokines and neurotrophic factors, which is called M2 microglial cells [6, 7]. Microglial polarization depends on the activation status, and maintaining the balance of microglial polarization is a foreground therapeutic option for stroke treatment [5, 8,9,10,11,12]
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