FcαRI-mediated neutrophil activation contributed to the pathogenesis of adult IgA vasculitis with nephritis

BACKGROUND: IgA vasculitis with nephritis (IgAV-N) is characterized by IgA-containing immune complex deposition. Neutrophilic infiltration is typically observed in skin lesions and may also occur in renal tissue. However, the mechanisms linking IgA-ICs and neutrophil activation remain unclear. The IgA Fc receptor (FcαRI), primarily expressed on neutrophils, plays a crucial role in regulating inflammatory responses to IgA. In this study, we explore the potential role of FcαRI-mediated neutrophil activation in the pathogenesis of IgAV-N. METHODS: Glomerular neutrophil infiltration was assessed by immunohistochemistry. FcαRI expression on neutrophils was analyzed in IgAV-N patients, IgA nephropathy patients, and healthy control participants by flow cytometry. Circulating IgA1-containing complexes (cIgA1 complexes) from IgAV-N patients or control participants were used to challenge neutrophils with/without FcαRI blockade (MIP8a). Neutrophil activation was measured by reactive oxygen species (ROS), neutrophil extracellular traps (NETs), lactoferrin production, and CD11b/CD62L expression. Endothelial injury was evaluated by ICAM-1 and VCAM-1 levels in neutrophil-endothelial cell co-cultures. RESULTS: Glomerular neutrophil infiltration correlated with endocapillary hypercellularity in IgAV-N. The expression of FcαRI on neutrophils was significantly elevated from IgAV-N patients, but not in IgAN. cIgA1 complexes derived from IgAV-N patients induced increased production of ROS, NETs, and lactoferrin from neutrophils compared to those from healthy control participants. These effects were attenuated by MIP8a. We also observed increased expression of CD11b and decreased expression of CD62L on neutrophils under cIgA1 complex challenge. In co-culture systems of neutrophils and endothelial cells, cIgA1 complexes increased ICAM-1 and VCAM-1 levels in supernatants, which were reduced by MIP8a. CONCLUSION: Our study demonstrated that in IgAV-N, pathogenic cIgA1 complexes induce FcαRI-mediated neutrophil activation, resulting in endothelial cell injury and contributing to IgAV-N pathogenesis. Blocking FcαRI significantly reduced neutrophil activation and subsequent endothelial cell damage in IgAV-N, suggesting that targeting FcαRI may serve as a potential intervention strategy.