Treatment with sitagliptin exacerbates the M2 phenotype in macrophages in vitro

Author(s)

Quadros-Pereira, Laura ; Nery-Neto, Jose Arimatea de Oliveira ; Da Silva, Eloisa Martins ; Doretto-Silva, Lorena ; Yariwake, Victor Yuji ; Camara, Niels Olsen ; Andrade-Oliveira, Vinicius

• Document type: Journal article
• Source: International Immunopharmacology; v. 145, p. 13-pg., 2024-12-10.

Abstract

Macrophages (M & Oslash;) 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 (Glucagonlike 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 M & Oslash;. Here, we aimed to investigate and characterize the effects of in vitro treatment with sitagliptin on M & Oslash; polarization. Bone marrow-derived M & Oslash; were differentiated with conditioned medium from the L929 cell line. For M1, M & Oslash; were stimulated with IFN-gamma and LPS, and for M2, with IL-4 and IL-13 for 24 h. Sitagliptin treatment was performed during M & Oslash; polarization. Polarized M & Oslash; 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-alpha. 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. (AU)

• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/03913-3 - Influence of obesity on the mechanisms of peripheral tolerance and on the modulation of immune response in the small intestine of mice.
• Grantee: Victor Yuji Yariwake
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/14755-0 - Shaping gut microbiota and immune system by the intestinal epithelial cells: from tissue homeostasis to diseases
• Grantee: Vinicius de Andrade Oliveira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/14388-4 - Incretin signal in tumor progression in the experimental model of Colorectal Cancer associated with Colitis
• Grantee: Eloisa Martins da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/08362-8 - Biology of enteroendocrine cells in homeostasis and during intestinal inflammation
• Grantee: José Arimatéa Oliveira Nery Neto
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/10908-6 - Enteroendocrine hormones and cells of the immune system: impact on the metabolism, differentiation, and function
• Grantee: Laura de Quadros Pereira
• Support Opportunities: Scholarships in Brazil - Master