The pathogenic roles of S100A8/A9 and S100A12 in antineutrophil cytoplasmic antibody-associated vasculitis

Abstract Background: The significance of S100A8/A9 and S100A12 in the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been clarified. In this study, the pathogenic role of S100A8/A9 and S100A12 in AAV were investigated.Results: Both serum and urine S100A8/A9 and S100A12 of AAV patients were excessively increased (compared with healthy controls, p<0.001), and were correlated with the activity and severity of disease. Serum S100A8/A9 was correlated with serum S100A12 (r=0.728, p<0.001), and there was also a relationship between urinary S100A8/A9 and S100A12 (r=0.536, p=0.001). In vitro study showed S100A8/A9 and S100A12 increased the chemotaxis index (CI) and the release of IL-1β, extended the life span, and enhanced the complement activation of ANCA-activated neutrophils. Blockade of TLR4 and RAGE inhibited the functions of S100A8/A9 and S100A12. Western-blotting showed p38 MAPK/NF-κB p65 pathway was involved in the influence of S100A8/A9 and S100A12 on ANCA-activated neutrophils. The effects of S100A8/A9 and S100A12 were reactive oxygen species (ROS)-independent because both S100A8/A9 and S100A12 did not enhance the ANCA-induced ROS and NETs generation.Conclusion: S100A8/A9 and S100A12 not only serve as markers for assessing the disease activity and severity, but also might take part into the pathogenesis of AAV directly.