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).