Treatment with sitagliptin exacerbates the M2 phenotype in macrophages in vitro

Macrophages (MØ) participate in the induction and the control of the host's immune response in homeostasis and during inflammatory diseases. Sitagliptin is a drug that inhibits the enzyme dipeptidyl peptidase 4 (DPP-4) and, therefore, increases the bioavailability of the incretins GIP (Gastric inhibitory polypeptide) and GLP-1 (Glucagon-like polypeptide). Thus, sitagliptin has been used to treat obesity and type II diabetes and has recently been associated with anti-inflammatory effects. It is known that the drug can modulate the immune response, however, the underlying mechanisms are not yet completely elucidated, including how they interfere with the activation and function of MØ. Here, we aimed to investigate and characterize the effects of in vitro treatment with sitagliptin on MØ polarization. Bone marrow-derived MØ were differentiated with conditioned medium from the L929 cell line. For M1, MØ were stimulated with IFN-γ and LPS, and for M2, with IL-4 and IL-13 for 24 h. Sitagliptin treatment was performed during MØ polarization. Polarized MØ were assessed for M1/M2 markers, DPP-4, GLP-1 and GIP receptors, mitochondrial dynamics and phagocytosis. Sitagliptin treatment exacerbates the M2 phenotype, featured by increased expression of CD206 and ARG1 and decreased gene expression levels of TNF-α. Sitagliptin-treated M2 altered mitochondrial dynamics with reduced membrane potential and mitochondrial reactive oxygen species production. These differences were accompanied by low gene expression levels of genes related to mitofusion, suggesting that sitagliptin treatment interferes with mitochondria function in M2, and exhibited less phagocytic capacity. In summary, our data suggest that sitagliptin exacerbates M2 profile in vitro.