TREM2 Drives Neutrophil Extracellular Traps‐Induced Dendritic Cell Maturation and Contributes to Lupus Progression

Abstract Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by hyperactive immune cells and excessive autoantigen accumulation. Dendritic cells (DC) can recognize multiple autoantigens and then leading to an inflammatory response, thereby playing a key role in the immunopathogenesis of SLE. However, the regulatory factors underlying DC function remain inadequately clarified. This study identifies that triggering receptor expressed on myeloid cells 2 (TREM2) is upregulated on DCs and is associated with SLE disease severity. Furthermore, TREM2 deficiency in DCs alleviates kidney damage and reduces serum anti‐dsDNA antibody levels, proteinuria, splenomegaly, and lymphadenopathy in lupus mice. Mechanistically, this study demonstrates that TREM2 recognizes neutrophil extracellular traps (NETs) to promote DC maturation and antigen presentation, thereby exacerbating the autoimmune response. More importantly, NETs‐derived myeloperoxidase (MPO) acts as a nonclassical ligand and interacts with TREM2 to activate DAP12/SYK/ERK. Subsequently, TREM2 facilitates NETs uptake by DCs, thereby activating the cGAS/STING signaling pathway. Inhibition of NETs formation or MPO effectively alleviates TREM2‐mediated lupus progression. Collectively, these findings reveal a novel modulatory role of TREM2 and NETs‐derived MPO in the pathogenesis of SLE, which may provide potential options for the treatment of SLE.