Sphingosine-1-phosphate and its receptors in anti-neutrophil cytoplasmic antibody-associated vasculitis.

Abstract

C5a plays a crucial role in anti-neutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. Our previous studies found that the interaction between sphingosine-1-phosphate (S1P) and C5a plays an important role in the ANCA-mediated activation of neutrophils. In the current study, the expression levels of S1P in plasma and its receptors (S1PR1-5) in kidneys were analysed in patients with ANCA-associated vasculitis (AAV). Plasma samples from 32 AAV patients in active stage and 20 AAV patients in remission were collected. The plasma levels of S1P were determined by an enzyme-linked immunosorbent assay (ELISA). The expression of S1PR1-5 in the renal specimens from 24 AAV patients was detected by immunohistochemistry. The associations of the plasma levels of S1P and renal expression of S1PRs with clinical and pathological parameters were analysed. The level of plasma S1P was significantly higher in AAV patients in active stage than it was in both patients in remission and in normal controls. Correlation analysis showed that the plasma levels of S1P correlated with the initial serum creatinine levels (r = 0.502, P = 0.003) and inversely correlated with the estimated glomerular filtration rate (eGFR; r = -0.358, P = 0.044) in AAV patients. Double-labelling immunofluorescence assay suggested that S1PR1-5 were expressed on endothelial cells in the glomeruli and that S1PR1, 4 and 5 were expressed on neutrophils. In AAV patients, the circulating S1P levels were elevated and the renal expression of S1PR2-5 was upregulated. The levels of circulating S1P and the renal expression of S1PR were associated with the renal involvement and disease activity of AAV.