Effect of metformin on human macrophage inflammatory response and phagocytosis of Mycobacterium tuberculosis
Cervantes, J.L.1, Sanca, A.3, Kositangool, P.1, Vargas, J.2, Gadhad, B.2, and Barragan, J.1
1 Laboratory for Education in Molecular Medicine, Department of Medical Education, and 2 Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso. El Paso, TX, U.S.A. 3 University of Texas El Paso, El Paso, TX, U.S.A.
Metformin (MTF) has a well-documented ability to control hyperglycemia, which has been shown to have effects on macrophage and lymphocyte functions that are key to controlling tuberculosis (TB) infection.
We aimed to better understand the effects of MTF on the response of human macrophages to Mycobacterium tuberculosis (Mtb).
PMA-differentiated THP-1 cells with two reporters for nuclear factor-ᴋB (NF-ᴋB), and interferon-regulatory factors (IRFs) were treated with 2mM of MTF for 4 hours, and then inoculated with Mtb from various lineages. Supernatants were tested with a multiplex ELISA system for 17 different analytes. Since MTF can also directly inhibit key metabolic processes of Mtb, we utilized gamma-irradiated mycobacteria. Phagocytosis was assessed by immunofluorescent assay.
Phagocytosis of all Mtb strains was increased in MTF-treated macrophages. A diminished NF-ᴋB activation after Mtb stimulation was observed in MTF-treated macrophages. There was no effect on 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 IL-10. Reduction in the expression of M1 polarization markers was observed in MTF-treated cells.
Our results indicate that MTF improves phagocytosis of Mtb by macrophages, while at the same time modulating their inflammatory response. Excessive inflammation is a phenomenon associated with active TB infection and with disruption of the granuloma architecture. MTF treatment could allow for improved activation of macrophages in the presence of TB infection. These results support the effects of MTF in key steps of TB infection control, and support its use as an additional treatment for TB.