NLRP3 Inflammasome Activity and Pyroptosis Are Involved in CD206+ Macrophage Activation by MPO Anti-Neutrophil Cytoplasmic Antibodies

• • NLRP3 expression is significantly elevated in kidneys of active AAV patients, with concomitant increases in cleaved caspase-1 and N-terminal GSDMD in PBMCs, indicating systemic inflammasome activation and pyroptosis; this provides a mechanistic biomarker for disease activity and a potential target for therapeutic intervention in ANCA-associated vasculitis. • • MPO-ANCA IgG purified from new-onset AAV patients induces NLRP3 inflammasome activation and IL-1β production in LPS-primed macrophages in vitro, an effect linked to increased MPO expression and JNK MAPK signaling pathway activation; this establishes a direct causal role for autoantibodies in macrophage-driven inflammation. • • Immunofluorescence analysis demonstrates partial colocalization of CD206 and NLRP3 in AAV kidneys, and silencing of MRC1 (encoding CD206) reduces inflammasome activation induced by MPO-ANCA IgG; this identifies CD206 as a critical mediator of the pathogenic cascade, offering a novel target for disrupting M2 macrophage-associated inflammation. • • The study employed primary human macrophages and patient-derived MPO-ANCA IgG, with statistical significance set at p < 0.05 (as per standard in the field), ensuring clinical relevance; these findings lay the groundwork for developing targeted therapies that inhibit NLRP3 or CD206 to mitigate AAV progression and improve patient outcomes.