Neutrophils impair B cell differentiation via mitochondrial and lipid metabolism in lupus

Summary Systemic lupus erythematosus (SLE) is characterised by aberrant neutrophil activation and pathogenic B-cell responses that drive organ damage, particularly in lupus nephritis (LN). Here, we identify neutrophil-derived mitochondrial DNA (mtDNA) as a metabolic driver of B-cell dysregulation in LN. Using single-cell transcriptomics of human blood and kidney tissue together with functional co-culture assays, we show that neutrophils from patients with active LN release extracellular traps enriched in mtDNA that induce mitochondrial oxidative stress in B cells. NET-derived mtDNA suppresses IL-10–producing regulatory B cells while promoting pro-inflammatory and plasmablast differentiation through nucleic acid–dependent signalling. Mechanistically, oxidative stress drives maladaptive NADPH utilisation, diverting NADPH from cholesterol biosynthesis toward antioxidant defence, resulting in altered lipid trafficking, mitochondrial dysfunction, and impaired regulatory B-cell differentiation. Consistent with this model, kidney B cells from patients with LN exhibit transcriptional signatures of disrupted redox and lipid metabolism, and NADPH deficiency is associated with reduced regulatory B-cell differentiation in humans. These findings identify a neutrophil-driven metabolic checkpoint that governs B-cell fate in lupus nephritis.