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The balance between keratinocyte proliferation and differentiation plays a decisive role for skin formation and development. Among the well-characterized biological mediators, insulin and sphingosine 1-phosphate (S1P) have been identified as major regulators of keratinocyte growth and differentiation. Insulin induces proliferation of keratinocytes, whereas S1P inhibits keratinocyte growth and initiates keratinocyte differentiation. However, it is not clear which S1P receptor subtype and downstream signaling pathways are involved in the antiproliferative action of S1P. In this study, we present evidence that S1P inhibits insulin-mediated keratinocyte growth via the activation of protein kinase C (PKC) followed by a subsequent dephosphorylation of Akt. The inhibition of insulin-mediated Akt activity by S1P is completely abolished in the presence of PKCdelta siRNA indicating that this isozyme is selectively potent at causing dephosphorylation of Akt and modifying keratinocyte proliferation. Further experiments by downregulation of S1P receptor subtypes and the use of specific receptor agonists/antagonists clearly indicated that the S1P(2) receptor is dominantly involved in the S1P-induced dephosphorylation of Akt and keratinocyte growth arrest. This is of great clinical interest, as the immunomodulator FTY720, after being phosphorylated by sphingosine kinase, activates all of the five S1P receptors except S1P(2) and therefore fails to inhibit keratinocyte proliferation.

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Background: Chronic kidney disease (CKD) is characterized by a sustained proinflammatory response of the immune system, promoting hypertension and cardiovascular disease. The underlying mechanisms are incompletely understood, but may be linked to gut dysbiosis. Dysbiosis has been described in adults with CKD; however, comorbidities limit CKD-specific conclusions. Methods: We analyzed the fecal microbiome, metabolites, and immune phenotypes in 48 children (normal kidney function, CKD stage G3-G4, G5 treated by hemodialysis (HD) or kidney transplantation) with a mean age of 10.6 ± 3.8 years. Results: Serum TNF-α and sCD14 were stage-dependently elevated, indicating inflammation, gut barrier dysfunction, and endotoxemia. We observed compositional and functional alterations of the microbiome, including diminished production of short-chain fatty acids. Plasma metabolite analysis revealed a stage-dependent increase of tryptophan metabolites of bacterial origin. Serum from HD patients activated the aryl hydrocarbon receptor and stimulated TNF-α production in monocytes, corresponding to a proinflammatory shift from classical to non classical and intermediate monocytes. Unsupervised analysis of T cells revealed a loss of mucosa-associated invariant T (MAIT) cells and regulatory T cell subtypes in HD patients. Conclusions: Gut barrier dysfunction and microbial metabolite imbalance apparently mediate the pro-inflammatory immune phenotype, thereby driving the susceptibility to cardiovascular disease. The data highlight the importance of the microbiota-immune axis in CKD, irrespective of confounding comorbidities.