Sphingosine‐1‐phosphate inhibits IL‐1‐induced expression of C‐C motif ligand 5viac‐Fos‐dependent suppression of IFN‐β amplification loop

Abstract

The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-κB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNβ production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-β amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells.

CCL5–Glutamate Cross-Talk in Astrocyte-Neuron Communication in Multiple Sclerosis

“…The expression and the release of CCL5 from astrocytes is tightly controlled by several receptor subtypes, including opioid receptors ( 49 , 50 ), group III metabotropic glutamate receptors ( 2 ), alpha/beta noradrenergic receptors ( 51 – 53 ), and sphingosine-1-phosphate receptor (S1PR) subtype 1 ( 54 ), as well as by endogenous neurotoxin such as quinolinic acid acting at NMDA receptors ( 55 ). These receptors represent targets of therapeutics for inflammatory autoimmune disease typified by overexpression of CCL5.…”

A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes)

“…To identify CNS cell types altered during neuroinflammatory processes, we developed an unbiased in vivo screen based on transcription of c-Fos (Bullitt, 1990), an immediate-early gene (IEG) that is rapidly transcribed in response to cellular stimuli, independent of de novo protein synthesis (Lau and Nathans, 1987). c-Fos can be activated in astrocytes (McNaughton and Hunt, 1992; Anderson et al, 1994; Morishita et al, 2011; Yester et al, 2015), microglia (Eun et al, 2004), and oligodendrocytes (Muir and Compston, 1996), as well as within neurons associated with memory (Matsuo et al, 2008). We adapted a conditional c-Fos reporter mouse that historically marks cells with nuclear GFP, which could be followed in four-dimensional (3D over time) analyses.…”

Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1

“…Although the mechanism by which SPHK1 suppresses STAT1 phosphorylation and downregulates total STAT1 levels remains to be further investigated, several pieces of evidence suggest that S1P might play an essential role. Indeed, recent studies have shown that activation of S1P 1 and S1P 2 by S1P suppresses IFN and STAT1 activity [77,78]. In addition, S1P binding to S1P 1 has also been shown to promote STAT3 activation [30,79,80], which is pro-tumorigenic in breast cancer [81].…”