S1P Receptor 1-Mediatd Elevated IL-6 Signaling Underlies Chronic Inflammation and Multiple Tissue Damage in Sickle Cell Disease

Objective-Sphingosine 1 phosphate (S1P) is a biolipid involved in chronic inflammation in multiple inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic genetic disorder associated with severe chronic inflammation. Here we evaluated the impact of S1P in chronic inflammation and underlying mechanisms in SCD.

Approach and Results-First, we demonstrated that interfering with S1P receptor signaling by FTY720, a FDA approved drug, significantly reduced systemic and local inflammation without anti-sickling effects. These findings led us to discover that IL-6 was highly elevated in the circulation and that increased S1P signaling via S1P receptors contributed to the induction of IL-6 in SCD mice. Genetic deletion of IL-6 in SCD significantly reduced local and systemic inflammation and multiple tissue damage and kidney dysfunction. Moreover, we determined that elevated IL-6 led to increased macrophage infiltration and elevated S1P1 gene expression in the macrophages of multiple tissues in SCD mice. Mechanistically, we reveled that S1P-S1P1 signaling reciprocally upregulated IL-6 gene expression in primary mouse macrophages in a JAK2-dependent manner.

Conclusion-Altogether, we revealed that elevated S1P signaling via S1P1-induced IL-6 is a key signaling network functioning as a malicious positive feed forward loop sustaining inflammation and promoting tissue damage in SCD. Our findings immediately highlight novel therapeutic possibilities.