Metformin Regulates the Inflammatory Response of Human Macrophages to Mycobacterium tuberculosis Through a Reduction of M1 Polarization

Abstract

Background: Besides its ability to control hyperglycemia, metformin (MTF) has effects on macrophage and lymphocyte functions, improving control of Mycobacterium tuberculosis (Mtb) infection and decreasing disease severity. We aimed to better understand the effects of MTF on human macrophages’ response to Mtb.

Methods: Phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells were treated with 2 mM of MTF for 4 h, and then inoculated with Mtb from various lineages. Since MTF can also directly inhibit key metabolic processes of Mtb, we utilized γ-irradiated mycobacteria. Phagocytosis was assessed by immunofluorescent assay. Supernatants were tested with a multiplex enzyme-linked immunosorbent assay (ELISA) system.

Results: Phagocytosis of all Mtb strains was increased in MTF-treated macrophages. A diminished nuclear factor-kappa B (NF-κB) activation after Mtb stimulation was observed in MTF-treated macrophages. There was no effect on interferon regulatory factor (IRF) activation by MTF pretreatment. Results from the multiplex ELISA showed a modulatory effect by MTF on the secretion of various pro-inflammatory cytokines, with no effect on anti-inflammatory cytokines. Reduction in the expression of M1 polarization markers was observed in MTF-treated cells upon Mtb stimulation.

Conclusions: Our results indicate that MTF improves phagocytosis of Mtb by macrophages, while at the same time modulating their inflammatory response. This occurs through a downshift of M1 polarization. Excessive inflammation is a phenomenon associated with active tuberculosis (TB) and with disruption of the granuloma architecture. MTF treatment could allow for an improved response of macrophages to Mtb infection. These results support the effects of MTF in key steps of Mtb infection control, and support its use as an additional treatment for TB.

Clin Infect Immun. 2021;6(2):40-46
doi: https://doi.org/10.14740/cii130