Neutrophil-derived LL37 mediates IgA nephropathy via NETs-dependent mechanism

IgAN is a common cause leading to end-stage renal disease. The deposition of pathogenic IgA in the glomerular mesangium is a critical step. However, the mechanisms of pathogenic IgA crossing the glomerular filtration barrier remain unclear. We hypothesized that neutrophil-derived LL37 is pathogenic and mediates IgAN through NETs-dependent mechanism. Serum LL37 were elevated in patients with active IgAN and correlated with poor long-term kidney survival (HR = 2.54). Functionally, LL37 is pathogenic in IgAN as mice lacking LL37 were protected from the development of severe IgAN by essentially reducing IgA and C3 deposition, mesangial cell proliferation, and proteinuria, which was reversed by neutrophils from WT but not from Cramp KO mice. Further study uncovered that LL37 were primarily derived from neutrophils as evidenced in Crampfl/flLy6gcre mice in which specific deletion of LL37 from neutrophils also suppressed the development of IgAN. With scRNA we found that LL37 acted via NETs to cause endothelials injury but increasing the permeability in mechanism, which was demonstrated by the addition of NETs, but not LL37-free NETs under high pIgA1 conditions in vivo and in vitro. LL37 is elevated in IgAN patients, derived from neutrophils, and plays a pathogenic role in IgAN via a NETs-dependent mechanism.