Fig. 2: Hypothetical mechanism by SARS-CoV-2 in establishing an inflammatory feedback loop between IL-6 and angiotensin II, copied from: (8)
Sphingosine-1-phosphate receptor 1 pathway:
Sphingosine-1-phosphate (S1P) 1 is a key signaling pathway that plays a role in regulating the inflammatory process; it involves lymphoid cells recruitment, vascular permeability and production of cytokines and chemokines. It exerts its functions after binding to its receptors; five G-protein-coupled receptors (S1PRs1–5) which exist in different types of cells (60).
The activation of S1P1 receptor which is usually bound to a G inhibitory protein and widely expressed on many types of cells leads to stimulation of Ras/ERK signaling pathway (61). Interestingly, the S1P1 receptor signaling was found to limit the immunopathological injury caused by both innate and adaptive responses, hence suppressing the cytokine storm formation following Influenza viral infection mainly through diminished production of IFN-α, CCL2, IL-6, TNFα, and IFN-γ which helped in decreasing the mortality rates in the infected mice (36). Similarly, in another study done later, it was found that stimulation of S1P1 has led to blockage of cytokines secretion and inhibited migration of inflammatory cells to the lungs of H1N1 influenza infected mice. It was demonstrated that these actions were exerted through reduction of cytokine storm independently of TLR3 and TLR7 signaling pathways but rather through targeting MyD88 (myeloid differentiation primary response gene 88)/TRIF (TIR-domain-containing adapter-inducing IFN-β) signaling which are main players in the NF-κB pathway (62).