Enhanced mTORC1 Signaling in Inflammatory Monocytes Links Systemic Inflammation to Cardiovascular Disease in...

Background/Objectives: Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA), not fully explained by traditional risk factors and disease activity alone. This study explored the relationship between circulating monocyte subsets, inflammatory cytokine profiles, and Mammalian Target of Rapamycin Complex (mTORC) signaling in RA patients with and without a history of CVD. Methods: Peripheral blood mononuclear cells from 9 RA patients with prior CVD, 9 carefully matched RA controls without CVD, and 6 healthy controls were analyzed by flow cytometry. Matching was rigorously conducted across clinically relevant variables, including age, sex, blood pressure, lipid profile, smoking status, RA duration, disease activity, Disease-Modifying Anti-Rheumatic Drug (DMARD) failures, and steroid use. Monocyte subsets were classified as inflammatory (CD14⁺HLA-DR⁺CCR2⁺) and non-inflammatory (CD14⁺CD163⁺CCR2^-). Results: RA-CVD⁺ patients exhibited higher frequencies of inflammatory monocytes and elevated intracellular levels of Interleukin 1 β (IL-1β) and Interleukin 6 (IL-6) compared to RA-CVD^- patients and healthy controls. mTORC activation, assessed by phosphorylation of S6 Ribosomal Protein (S6Rp), was significantly increased in inflammatory monocytes from RA-CVD⁺ patients. Conclusions: S6Rp correlated with IL-1β and IL-6 levels only in the RA-CVD⁺ group, suggesting a link between mTORC activity and inflammatory monocyte function. Notably, these inflammatory features did not correlate with disease activity scores or disease duration. We observed increased mTORC1 signaling in inflammatory monocytes in RA-CVD⁺ patients, suggesting a potential association with cardiovascular comorbidity.