Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens. Neutrophils contribute to disease pathogenesis by releasing self-DNA–peptide complexes, which activate pDCs via Toll-like receptor 9 (TLR9). These complexes, formed by neutrophil-derived antimicrobial peptides (e.g., LL37 and HNPs) and self-DNA, are released as neutrophil extracellular traps (NETs) and trigger innate immune responses. SLE patients develop autoantibodies against these complexes, leading to chronic pDC activation and autoimmunity. The study identifies a key mechanism in which neutrophils release immunogenic complexes that activate pDCs and promote autoantibody production. This process is enhanced by autoantibodies that facilitate the internalization of self-DNA complexes into pDCs, leading to sustained IFN-α production and disease progression. The findings highlight the role of neutrophils in SLE pathogenesis and suggest new therapeutic targets for treating this autoimmune disease.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens. Neutrophils contribute to disease pathogenesis by releasing self-DNA–peptide complexes, which activate pDCs via Toll-like receptor 9 (TLR9). These complexes, formed by neutrophil-derived antimicrobial peptides (e.g., LL37 and HNPs) and self-DNA, are released as neutrophil extracellular traps (NETs) and trigger innate immune responses. SLE patients develop autoantibodies against these complexes, leading to chronic pDC activation and autoimmunity. The study identifies a key mechanism in which neutrophils release immunogenic complexes that activate pDCs and promote autoantibody production. This process is enhanced by autoantibodies that facilitate the internalization of self-DNA complexes into pDCs, leading to sustained IFN-α production and disease progression. The findings highlight the role of neutrophils in SLE pathogenesis and suggest new therapeutic targets for treating this autoimmune disease.