Cell-intrinsic sphingosine kinase 2 promotes macrophage polarization and renal inflammation in response to unilateral ureteral obstruction

Abstract

Sphingosine Kinase-2 (Sphk2) is responsible for the production of the bioactive lipid Sphingosine-1 Phosphate, a key regulator of tissue repair. Here we address the in vivo significance of Sphingosine Kinase -2 in renal inflammation/fibrosis in response to unilateral ureteral obstruction using both genetic and pharmacological strategies. Obstructed kidneys of Sphk2-/- mice showed reduced renal damage and diminished levels of the renal injury markers TGFβ1 and αSMA when compared to wild type controls. We found a consistently significant increase in anti-inflammatory (M2) macrophages in obstructed Sphk2-/- kidneys by flow cytometry and a decrease in mRNA levels of the inflammatory cytokines, MCP1, TNFα, CXCL1 and ILβ1, suggesting an anti-inflammatory bias in the absence of Sphk2. Indeed, metabolic profiling showed that the pro-inflammatory glycolytic pathway is largely inactive in Sphk2-/- bone marrow-derived macrophages. Furthermore, treatment with the M2-promoting cytokines IL-4 or IL-13 demonstrated that macrophages lacking Sphk2 polarized more efficiently to the M2 phenotype than wild type cells. Bone marrow transplant studies indicated that expression of Sphk2-/- on either the hematopoietic or parenchymal cells did not fully rescue the pro-healing phenotype, confirming that both infiltrating M2-macrophages and the kidney microenvironment contribute to the damaging Sphk2 effects. Importantly, obstructed kidneys from mice treated with an Sphk2 inhibitor recapitulated findings in the genetic model. These results demonstrate that reducing Sphk2 activity by genetic or pharmacological manipulation markedly decreases inflammatory and fibrotic responses to obstruction, resulting in diminished renal injury and supporting Sphk2 as a novel driver of the pro-inflammatory macrophage phenotype.

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

“…More specifically, SPHK1/2 KD is involved in the inhibition of IL-6 production in MCF7 cells, thus reducing cancer-mediated inflammation. Our data correlate with a previous finding in which SPHK1 inhibition lowered the production of inflammatory mediators such as TNF-α, IL-6, IL-1β, whereas SPHK2 inhibition lowered the production of TNF-α and IL-1β in macrophages [75,76]. Overall, SPHK1/2 are inflammatory, and hence inhibition of SPHK1/2 decreases cancer-mediated inflammation.…”

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

“…BDNF enriched in glioma environment stimulated the production of IL-15 in CD11b + macrophages cells and altered macrophage plasticity ( 74 ). Sphk2 was demonstrated as a novel driver of the pro-inflammatory macrophage phenotype ( 75 ). IRS2 negatively regulates YM1 protein induction in macrophages and negatively regulated alternative macrophage activation ( 76 ).…”

Sphingosine-1-Phosphate and Macrophage Biology—How the Sphinx Tames the Big Eater

“…Besides promoting M1-like cytokine production, an increase in anti-inflammatory macrophages was reported in SPHK2-deficient obstructed kidneys. Treating SPHK2-deficient murine BMDM with IL-4 or IL-13 induced a more pronounced M2 profile compared to wild type macrophages (125). Thus, macrophage SPHK2 may restrict M1 as well as M2 activation.…”

“…For renal macrophages protection toward fibrosis was linked to SPHK2-dependent S1P signaling. SPHK2-deficient kidney-resident macrophages shifted toward the M2 phenotype due to changes in the glycolytic pathway, which reduced renal fibrosis by lowering the production of pro-inflammatory cytokines such as IL-1β and TNF-α (125). Evidently, S1P contributes to macrophage-dependent fibrotic responses by shaping their activation, particularly the release of pro-fibrotic cytokines/chemokines such as TGF-ß, IL-13, or CCL2.…”