Metformin effect on human macrophage inflammatory response and phagocytosis of Mycobacterium tuberculosis

Abstract

Abstract Metformin (MTF) has a well-documented ability to cfontrol hyperglycemia, which has been shown to have effects on macrophage and lymphocyte functions that are key to controlling tuberculosis (TB) infection. Here, we aimed to better understand the effects of MTF on the phagocytosis of Mycobacterium tuberculosis (Mtb) by human macrophages. PMA-differentiated THP-1 cells with two reporters for nuclear factor-κB (NF-κB), and interferon-regulatory factors (IRFs) were treated with 2mM of MTF for 4 hours, and then inoculated with Mtb from various lineages. Since MTF can also directly inhibit key metabolic processes of Mtb, we controlled this variable by using of gamma-irradiated mycobacteria. Phagocytosis was assessed by immunofluorescent assay. Phagocytosis of Mtb increased in MTF-treated macrophages. NF-κB activation after Mtb stimulation was lower in MTF-treated macrophages. The effect on IRF activation was minimal. Our results indicate that MTF improves phagocytosis of Mtb by macrophages, while it at the same time modulating their inflammatory response. Downregulation of type I IFN pathways, associated with active TB infection, could allow for improved activation of macrophages in the presence of TB infection. These results support the effects of MTF in keys steps TB infection control, and support its use as an additional treatment for TB.