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. 2021 Oct 19;12:733387. doi: 10.3389/fphar.2021.733387

FIGURE 2.

FIGURE 2

The role of SphK1 in inflammation immune-related diseases. SphK1 is over-expressed in a variety of inflammation immune-related diseases. Hypertension caused by the production of cytokines and various stimuli is accompanied by the activation of the immune system. In the inflammatory environment, the up-regulated SphK1 is involved in the recruitment of T lymphocytes to the inflammatory site, the release of inflammatory cytokines, and the vascular injury caused by the reduction of NO release in the pathogenesis of hypertension. As SphK1 is abnormally activated, SphK1 inhibition (such as PF-543) can effectively reduce blood pressure. Atherosclerosis is accompanied by the activation of the immune system. SphK1 activated by TNF-α promotes the differentiation of macrophage-like cells in immune cells, produces cell adhesion molecules and superoxide, and the proliferation of VSMCs. SphK1 over-expressed in ECs regulates the release of NO for vasoconstriction, which is the cause of vascular inflammation. SphK1 is over-expressed in activated microglia, promotes the release of pro-inflammatory mediators, and causes neuroinflammation and neuronal apoptosis in AD. Whereas SPM reduction is associated with down-regulated SphK1 in neurons, aggravating neuroinflammation which may be due to sphingolipid-rheostat modulation. SphK1 over-expression activates immune cells to release cytokines in the IEC of IBD caused by genetic and environmental factors. When developing into CAC, SphK1 induces the expression of pro-inflammatory markers and immune cell infiltration, which can be alleviated by SphK1 inhibition (such as LCL351). SphK1/S1P forms a positive feedback with downstream IL-6/STAT3 to maintain the proliferation of IEC. SphK1 is abnormally over-expressed in the synovitis microenvironment of RA, participates in FLS proliferation, the release of inflammatory cytokines, and inflammatory cell infiltration. Over-expression of SphK1 mediates the proliferation of ECs and forms neovascularization, which may be related to VEGF/SphK1/S1P signal. SphK1 inhibition (such as PF-543) can improve synovial microvascular angiogenesis.