Abstract
Tuberculosis (TB) is a global public health problem, which is caused by Mycobacterium tuberculosis (Mtb). Type 2 diabetes mellitus (T2DM) is one of the leading predisposing factors for development of TB after HIV/AIDS. Glibenclamide is a widely used anti-diabetic drug in low and middle-income countries where the incidence of TB is very high. In a human macrophage cell line, glibenclamide, a K+ATP-channel blocker, promoted alternative activation of macrophages by enhancing expression of the M2 marker CD206 during M2 polarization. M2 macrophages are considered poorly microbicidal and associated with TB susceptibility. Here, we investigated the effect of glibenclamide on M1 and M2 phenotypes of primary human monocytes and further determined whether specific drug treatment for T2DM individuals influences the antibacterial function of monocytes in response to mycobacterial infection. We found that glibenclamide significantly reduced M1 (HLA-DR+ and CD86+) surface markers and TNF-α production on primary human monocytes against mycobacterial infection. In contrast, M2 (CD163+ and CD206+) surface markers and IL-10 production were enhanced by pretreatment with glibenclamide. Additionally, reduction of bactericidal activity also occurred when primary human monocytes from T2DM individuals who were being treated with glibenclamide were infected with Mtb in vitro, consistent with the cytokine responses. We conclude that glibenclamide reduces M1 and promotes M2 polarization leading to impaired bactericidal ability of primary human monocytes of T2DM individuals in response to Mtb and may lead to increased susceptibility of T2DM individuals to TB and other bacterial infectious diseases.
Highlights
Tuberculosis (TB) is a global public health problem, which is the leading cause of death due to a single infectious agent, Mycobacterium tuberculosis (Mtb)
Because the peripheral lipid portion of the cell wall is very similar between Bacille CalmetteGuerin (BCG) and Mtb [25], it is predicted that their ability to infect peripheral monocytes or macrophages is similar
To determine the effect of glibenclamide on M1 and M2 marker expression, purified primary monocytes from healthy control individuals were pretreated with the drug at doses comparable to the range of glibenclamide given during oral therapy to human patients [26, 27], prior to infection with BCG
Summary
Tuberculosis (TB) is a global public health problem, which is the leading cause of death due to a single infectious agent, Mycobacterium tuberculosis (Mtb). The predictive factors for TB among those with DM are HIV co-infection, age (older than 45), overweight, poor glycemic control, and being male [5, 6] This underlying immunological mechanisms are still poorly understood. The drug acts by binding to and inhibiting the ATP-sensitive potassium channel (KATP) inhibitory regulatory subunit sulfonylurea receptor 1 (SUR1) in pancreatic beta cells, increases the plasma insulin concentrations [8]. This drug lowers blood glucose concentrations by about 20% and HbA1c by 1–2% [9]. Our previous study showed that glibenclamide has potent and wide-ranging effects on cell mediated immune responses including reduced neutrophil pro-inflammatory cytokine production, migration, and killing in response to another intracellular bacteria, Burkholderia pseudomallei [11, 12]
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