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

## TL;DR

This study shows how TREM2 and neutrophil extracellular traps worsen lupus by triggering immune responses and suggests targeting these could help treat the disease.

## Contribution

The study reveals TREM2's novel role in lupus progression by linking it to neutrophil extracellular traps and specific signaling pathways.

## Key findings

- TREM2 deficiency in dendritic cells reduces lupus symptoms in mice.
- TREM2 recognizes MPO from neutrophil extracellular traps to activate immune signaling pathways.
- Blocking neutrophil extracellular traps or MPO inhibits lupus progression in TREM2-dependent manner.

## 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.

TREM2 recognizes NETs‐derived MPO to promote DC maturation and antigen presentation, thereby exacerbating the autoimmune response in SLE. Mechanistically, TREM2 activation triggers the DAP12/SYK/ERK cascade and enhances NETs internalization by DCs, which in turn activates the cGAS/STING signaling pathway. Collectively, this study demonstrates that TREM2 drives SLE pathogenesis by sequentially initiating two key signaling events.