Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

Abstract

Microglia mediated responses to neuronal damage in the form of neuroinflammation is a common thread propagating neuropathology. In this study, we investigated the microglial alterations occurring as a result of sphingosine 1‐phosphate (S1P) accumulation in neural cells. We evidenced increased microglial activation in the brains of neural S1P‐lyase (SGPL1) ablated mice (SGPL1fl/fl/Nes) as shown by an activated and deramified morphology and increased activation markers on microglia. In addition, an increase of pro‐inflammatory cytokines in sorted and primary cultured microglia generated from SGPL1 deficient mice was noticed. Further, we assessed autophagy, one of the major mechanisms in the brain that keeps inflammation in check. Indeed, microglial inflammation was accompanied by defective microglial autophagy in SGPL1 ablated mice. Rescuing autophagy by treatment with rapamycin was sufficient to decrease interleukin 6 (IL‐6) but not tumor necrosis factor (TNF) secretion in cultured microglia. Rapamycin mediated decrease of IL‐6 secretion suggests a particular mechanistic target of rapamycin (mTOR)‐IL‐6 link and appeared to be microglia specific. Using pharmacological inhibitors of the major receptors of S1P expressed in the microglia, we identified S1P receptor 2 (S1PR2) as the mediator of both impaired autophagy and proinflammatory effects. In line with these results, the addition of exogenous S1P to BV2 microglial cells showed similar effects as those observed in the genetic knock out of SGPL1 in the neural cells. In summary, we show a novel role of the S1P‐S1PR2 axis in the microglia of mice with neural‐targeted SGPL1 ablation and in BV2 microglial cell line exogenously treated with S1P.

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

“…Outside of the tumor setting, mice without S1P lyase expression had greater microglial activation in the brain. The accumulation of S1P signaled through S1PR2 to mediate this inflammation [ 160 ]. Figure 4 shows an overview of the alterations in both the adaptive and innate immune cells in GBM and metastatic cancers.…”

Neurodegeneration Caused by S1P-Lyase Deficiency Involves Calcium-Dependent Tau Pathology and Abnormal Histone Acetylation

“…SGPL1 deficiency in brain has been shown to affect neuronal health and to cause neuroinflammation accompanied by impairment of cognitive and motor skills in mice [ 17 , 18 , 28 ]. The central aim of the present study was to further unravel the molecular bases of the neurological phenotype of SGPL1 fl/fl/Nes mice.…”

“…On the other hand, apart from hyperphosphorylation, microglial activation and thus neuroinflammation appear to be essential for astrocytic tau pathology [ 30 ]. We have recently shown that in SGPL1 fl/fl/Nes mice, microglial activation and hence release of pro-inflammatory cytokines including interleukin (IL) 6 (IL-6) and tumor necrosis factor alpha (TNF-α), is caused by S1P released from SGPL1-deficient astrocytes [ 28 ]. Whether and how these factors are involved in the tau hyperphosphorylation of SGPL1-deficient astrocytes has to be clarified in future studies.…”

P2X7R-mediated Autophagic Impairment Contributes to Central Sensitization in a chronic Migraine Model with Recurrent Nitroglycerin Stimulation in Mice

“…However, no studies have examined this mechanism in migraine. It is well documented that autophagic ux can affect the microglial phenotypes and guide the in ammation into a protective or detrimental state [123][124][125][126]. The enhanced autophagy has been reported to induce activation of M1 phenotype microglia and promote the release of pro-in ammatory cytokines.…”