Metformin treatment of juvenile mice potentiates innate immune response to bacterial lipopolysaccharide in males

Objective: Metformin is a widely used drug, with a good safety profile, for treatment of type 2 diabetes. Recently, it has been found to also exhibit immunomodulatory potential. Weaim to preliminarily explore the potential role of metformin in regulating innate immunity using UM-HET3 mice. Methods: In this study, we treated juvenile UM-HET3 mice with metformin and investigated the alteration of the innate immune response. Peripheral blood of HET3 mice was treated with ex-vivo lipopolysaccharide (LPS) stimulation to induce a leukocyte inflammatory response, which was detected by analyzing the expression of LPS receptors TLR4 and CD14 on leukocytes with flow cytometry. Furthermore, cytokine release induced by LPS was measured in isolated cell culture supernatants with ELISA. Results: In this study LPS treatment triggered a downregulation of TLR4 as well as an upregulation of CD14 expressed on the cell surface. Besides, it enhanced the secretion of pro-inflammatory cytokines TNF-alpha, IL-1 ss and IL-6. The results showed that metformin treatment led to a significant (p <.05) increase in the expression of CD14 and pro-inflammatory cytokines, including IL-1 ss and IL-6, as well as increased proportion of TLR4 downregulation on the cell surface in response to LPS, specifically in males. Conclusions: This study indicates that treating juvenile mice with metformin enhances the innate immune response to bacterial endotoxin in males, but not in females.