Abstract
Sphingosine 1-phosphate (S1P) is involved in a wide range of cellular processes, which include proliferation, apoptosis, lymphocyte egress, endothelial barrier function, angiogenesis, and inflammation. S1P is produced by two isoenzymes, namely, sphingosine kinase 1 and 2 (SphK1 and 2) and once produced, S1P can act both in an autocrine and paracrine manner. S1P can be dephosphorylated back to sphingosine by two phosphatases (SGPP 1 and 2) or can be irreversibly cleaved by S1P lyase. S1P has a diverse range of functions, which is mediated in a receptor dependent, through G-protein coupled receptors (S1PR1–5) or receptor independent manner, through intracellular targets such as HDACs and TRAF2. The involvement of S1P signaling has been confirmed in various disease conditions including lung diseases. The SphK inhibitors and S1PR modulators are currently under clinical trials for different pathophysiological conditions. There is a significant effort in targeting various components of S1P signaling for several diseases. This review focuses on the ways in which S1P signaling can be therapeutically targeted in lung disorders.
Highlights
Sphingolipids are ubiquitous components of the cell membrane and provide structural integrity
One of the simplest structural sphingolipids, is converted to sphingosine which in turn is phosphorylated by two isoenzyme specific kinases, namely, SphK1 and 2 to form sphingosine 1-phosphate (S1P) [1,2,3]
There is a tight regulation of formation and degradation of S1P within the cells, through activation of SphKs to form S1P, dephosphorylation by phosphatases (SPPs) or degradation by S1P lyase (SPL) (Figure 1)
Summary
Sphingolipids are ubiquitous components of the cell membrane and provide structural integrity. An isoenzyme specific inhibitor of SphK1 (SK1-I) decreased airway hyperresponsiveness (AHR) and inflammation in a mast cell-dependent murine model of allergic asthma [21]. These ganglions express TRPV1 ion channel and intensify broncho constrictions very similar to that seen in asthma in sensitized lungs [26] Transcriptomic analysis of these cells revealed one of the abundant transcripts as S1PR3 [26] and further confirmatory studies indicated that S1P is one of the signals involved in the cross talk between immune cell activity and neurons in asthmatic responses. FTY720 reduced the ORMDL3 expression, AHR and associated inflammation, and mucus production and elevated the ceramide levels in house dust mite-induced lung inflammation model in mice, further confirming the potential beneficial role of FTY720 in the treatment of asthma [29]. It was shown that DSCG inhibited asthmalike features induced by S1P in mice as seen from the reduced recruitment of mast cells and B cells to lungs, decrease in AHR, and inflammation [31]
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