Abstract
Sphingosine-1-phosphate (S1P) is a pleiotropic sphingolipid derived by the phosphorylation of sphingosine either by sphingosine kinase 1 (SPHK1) or SPHK2. Importantly, S1P acts through five different types of G-protein coupled S1P receptors (S1PRs) in immune cells to elicit inflammation and other immunological processes by enhancing the production of various cytokines, chemokines, and growth factors. The airway inflammation in asthma and other respiratory diseases is augmented by the activation of immune cells and the induction of T-helper cell type 2 (Th2)-associated cytokines and chemokines. Therefore, studying the S1P mediated signaling in airway inflammation is crucial to formulate effective treatment and management strategies for asthma and other respiratory diseases. The central aim of this study is to characterize the molecular targets induced through the S1P/S1PR axis and dissect the therapeutic importance of this key axis in asthma, airway inflammation, and other related respiratory diseases. To achieve this, we have adopted both high throughput next-generation knowledge discovery platforms such as SwissTargetPrediction, WebGestalt, Open Targets Platform, and Ingenuity Pathway Analysis (Qiagen, United States) to delineate the molecular targets of S1P and further validated the upstream regulators of S1P signaling using cutting edge multiple analyte profiling (xMAP) technology (Luminex Corporation, United States) to define the importance of S1P signaling in asthma and other respiratory diseases in humans.
Highlights
Sphingosine-1-phosphate (S1P), a sphingolipid, is one of the essential modulators of various cellular processes such as differentiation, survival, growth, etc. (Aarthi et al, 2011)
In the SwissTargetPrediction web tool, the predictions are performed from analogous molecules in 2D and 3D, from 376342 experimentally active compounds that are significantly interacting with 3068 known macromolecular targets (Daina and Zoete, 2019)
The SwissTargetPrediction was performed for S1P (C18H38NO5P) using both Canonical [CCCCCCCCCCCCCC = CC(C(COP( = O)(O)O)N)O] and Isomeric (CCCCCCCCCCCCC/C = C/[C@H]([C@H](COP( = O) (O)O)N)O) Simplified Molecular Input Line Entry System (SMILES) codes (Supplementary Figure S1) computed by OEChem (Version 2.1.5), have shown that it interacts with 64 and 93 molecules respectively (Tables 1A,B) with the highest percentage of binding (46.7 and 53.3%, respectively) with Family A G-protein coupled receptors (GPCRs) (Figure 1)
Summary
Sphingosine-1-phosphate (S1P), a sphingolipid, is one of the essential modulators of various cellular processes such as differentiation, survival, growth, etc. (Aarthi et al, 2011). Sphingolipids are recently termed as "morphogenetic lipids" for their crucial role in embryonic stem cell differentiation, survival, and postnatal development (Wang et al, 2018). 1000 people die each day due to Asthma and there were 339.4 million people affected by asthma globally in 2016. This represents a 3.6% increase in age-standardized prevalence since 2006 (Global Asthma Network, 2018; Global Initiative for Asthma, 2018). Asthma affects individuals of all ages and all ethnicity and the economic burden of respiratory diseases to governments, healthcare systems, families, and patients are on the rise globally (Singh, 2005; Ellwood et al, 2017). Creating new applied scientific knowledge in the area of asthma and related respiratory diseases has become a key priority around the globe (Ellwood et al, 2017; Koshak et al, 2017)
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