TLR2 reprograms glucose metabolism in CD4⁺ T cells of rheumatoid arthritis patients to mediate cell hyperactivation and TNF-α secretion

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which activated CD4⁺ T cells participate in the disease process by inducing inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) on CD4⁺ T cells in RA patients, and to elucidate the underlying mechanisms by which TLR2 contributes to the pathogenesis of RA.

Serum samples were collected from RA patients and healthy controls. Soluble TLR2 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to assess the TLR2 expression level, activation status, cytokine production, reactive oxygen species (ROS) levels, and glucose uptake capacity of CD4⁺ T cells. Quantitative polymerase chain reaction (qPCR) was used to measure the expression of enzymes associated with glucose and lipid metabolism. The concentration of lactic acid in the culture supernatant was determined using a dedicated detection kit.

RA patients had higher levels of TLR2 in their serum, which positively correlated with C-reactive protein and rheumatoid factor. The expression level of TLR2 in CD4⁺ T cells of RA patients was increased, and TLR2⁺ cells showed higher activation levels than TLR2- cells. Activation of TLR2 in CD4⁺ T cells of RA patients promoted their activation, TNF-α secretion, and increased production of ROS. Furthermore, TLR2 activation led to changes in enzymes related to glucose metabolism, causing a shift in glucose metabolism towards the pentose phosphate pathway. Blocking oxidative phosphorylation and the pentose phosphate pathway had varying effects on CD4⁺ T cell function.

TLR2 reprograms the glucose metabolism of CD4⁺ T cells in RA patients, contributing to the development of RA through ROS-mediated cell hyperactivation and TNF-α secretion.