A neutrophil-mesangial cell axis promotes glomerular injury in lupus nephritis

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE), yet the mechanisms linking neutrophil activation to early kidney damage remain elusive. We aimed to elucidate the role of neutrophils and neutrophil extracellular traps (NETs) in driving mesangial cell (MC) activation during LN progression.

Histology and flow cytometry were performed in NZB/W F₁ and C57/BL6 mice to evaluate neutrophil dynamics throughout LN development. Human LN kidney biopsies were analysed for NETs and neutrophil infiltration. In vitro, human MCs were stimulated with either NETs or purified citrullinated histone H3 (citH3), followed by assessment via enzyme-linked immunosorbent assay and RNA sequencing. Plasma levels of NET remnants (citH3-DNA complexes) were measured in patients with SLE and correlated with clinical parameters.

In NZB/W F₁ mice, NETs progressively accumulated in mesangial regions before proteinuria onset and correlated nephritis severity and mesangial expansion. Similar NET deposition was observed in human LN biopsies. MCs internalised NETs in vitro, leading to enhanced proliferation. CitH3 induced Toll-like receptor 4 dependent MC activation, resulting in increased proinflammatory cytokines, type I interferon-stimulated genes, and collagen IV expression. Transcriptomic profiling of citH3-stimulated MCs revealed overlap with mesangial gene signatures in childhood-onset LN kidneys. Plasma citH3-DNA complex levels were elevated in patients with active LN and correlated with systemic lupus erythematosus disease activity index, hypocomplementemia, renal and musculoskeletal involvement.

NET-producing neutrophils infiltrate the kidney early in LN. NET-derived citH3 activates MC through Toll-like receptor 4, promoting inflammation and fibrosis, establishing a novel NET-MC axis that may represent a mechanistic driver and therapeutic target in LN.