Macrophage extracellular traps in autoimmunity: In vivo definition, pathogenic circuits, and therapeutic targeting

Although neutrophil extracellular traps are well documented in autoimmune diseases, the pathogenic relevance of macrophage extracellular traps (METs) has been less well defined. METs are chromatin-based extracellular scaffolds that extend beyond antimicrobial defense to organize inflammation, concentrate danger signals, and externalize autoantigens. Accumulating preclinical and clinical evidence links increased MET burden to autoimmune activity and organ injury, consistent with a potential disease-amplifying contribution in selected contexts rather than a mere epiphenomenon. By exposing a broad antigenic repertoire—including modified chromatin (e.g., citrullinated histones in specific contexts) and mitochondrial DNA, METs may contribute to hallmark autoantibody responses such as ACPA, anti-dsDNA, and ANCA, and may sustain nucleic-acid–driven inflammatory programs. In this review, we conceptualize METs as a candidate integrative innate immune module that connects autoantigen presentation with fibro-inflammatory remodeling across rheumatoid arthritis, systemic lupus erythematosus, ANCA-associated vasculitis, and ulcerative colitis. We further propose a pragmatic in vivo identification and reporting checklist to reduce NET/MET misclassification and improve cross-study comparability. Finally, we outline three therapeutic axes—limiting MET induction, accelerating scaffold dismantling/clearance, and dampening DNA-sensing—and discuss translational constraints (host-defense trade-offs and biomarker-guided selection). Together, this synthesis provides a framework to prioritize mechanistic questions and accelerate biomarker and drug-development efforts targeting MET-driven pathology. • Proposes lineage-resolved in vivo criteria to improve NET/MET attribution in mixed lesions. • Frames MET formation as stimulus- and state-conditioned, with evidence-based interpretive boundaries. • Summarizes current evidence linking MET-associated cargo to autoantigen exposure and nucleic-acid inflammation. • Outlines therapeutic considerations across MET induction, scaffold handling, and DNA-sensing pathways. • Highlights translational considerations, including host-defense balance and biomarker-informed stratification.