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

Area of Science:

• Immunology
• Rheumatology
• Autoimmune Diseases

Background:

• Systemic lupus erythematosus (SLE) is a severe autoimmune disease driven by immune dysregulation.
• Dendritic cells (DCs) play a critical role in SLE pathogenesis by presenting autoantigens.
• Regulatory factors controlling DC function in SLE are not fully understood.

Purpose of the Study:

• To investigate the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in the function of dendritic cells in SLE.
• To elucidate the mechanisms by which TREM2 influences SLE progression.

Main Methods:

• Analysis of TREM2 expression in DCs from SLE patients and lupus mouse models.
• Genetic deficiency of TREM2 in DCs of lupus mice.
• Investigation of TREM2 interaction with neutrophil extracellular traps (NETs) and myeloperoxidase (MPO).
• Assessment of signaling pathways including DAP12/SYK/ERK and cGAS/STING.
• Evaluation of therapeutic interventions targeting NETs formation or MPO.

Main Results:

• TREM2 is upregulated on DCs and correlates with SLE severity.
• TREM2 deficiency in DCs ameliorates kidney damage, autoantibody production, and systemic inflammation in lupus mice.
• TREM2 recognizes NETs-derived MPO, activating the DAP12/SYK/ERK pathway and promoting DC maturation.
• TREM2 facilitates NETs uptake by DCs, activating the cGAS/STING pathway.
• Inhibition of NETs formation or MPO activity reduces TREM2-mediated lupus exacerbation.

Conclusions:

• TREM2 on DCs plays a significant role in SLE pathogenesis by recognizing NETs and MPO.
• The TREM2-NETs-MPO axis promotes DC activation and exacerbates autoimmune responses in SLE.
• Targeting TREM2, NETs, or MPO presents a potential therapeutic strategy for SLE.