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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\u2010dsDNA 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\u2010derived 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\u2010mediated lupus progression. Collectively, these findings reveal a novel modulatory role of TREM2 and NETs\u2010derived MPO in the pathogenesis of SLE, which may provide potential options for the treatment of SLE.<\/jats:p>","DOI":"10.1002\/advs.202508938","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T05:51:07Z","timestamp":1763963467000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["TREM2 Drives Neutrophil Extracellular Traps\u2010Induced Dendritic Cell Maturation and Contributes to Lupus Progression"],"prefix":"10.1002","volume":"13","author":[{"given":"Jingxian","family":"Shu","sequence":"first","affiliation":[{"name":"Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging The Fifth Affiliated Hospital of Sun Yat\u2010sen University  Zhuhai 519000 China"},{"name":"Department of pharmacy The Fifth Affiliated Hospital of Sun Yat\u2010sen University  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