Rheumatoid arthritis synovial fibroblasts promote the glycolysis of myeloid-derived suppressor cells via TREM1/mTOR axis

Myeloid-derived suppressor cells (MDSCs) are pathologically expanded in rheumatoid arthritis (RA), yet the underlying metabolic drivers remain elusive. Single-cell RNA Sequencing (scRNA-seq) and flow cytometry (FC) were systematically performed to characterize metabolic reprogramming in MDSCs from RA patients. Spatial transcriptomics was used to map in situ cell distributions within synovial tissue. The regulatory effects of human RA fibroblast-like synoviocytes (FLSs) MH7a cells on MDSCs glycolysis were validated by detecting the extracellular acidification rate, glucose uptake capacity and lactate production. Pharmacological inhibitors were employed to interrogate the pathway for orchestrating glycolytic reprogramming of RA-MDSCs. We found that RA-MDSCs underwent glycolytic reprogramming during differentiation, which directly potentiated their inflammatory phenotype. Mechanistically, RA-FLSs induced triggering receptor expressed on myeloid cell 1 (TREM1) overexpression in MDSCs through direct cell-cell contact, initiating a PI3K-AKT-mTOR-HIF-1α signaling cascade that fueled glycolytic flux. Pharmacological blockade of TREM1 not only attenuated inflammatory monocytic MDSCs (M-MDSCs) differentiation, but also restored the suppressive activity of MDSCs. Our results established a critical role for TREM1 signaling in mediating the FLSs-MDSC crosstalk in RA, which unveiled TREM1 as a therapeutic target to restore MDSC metabolic homeostasis in autoimmune arthritis.