Inhibiting Histone Deacetylases in Human Macrophages Promotes Glycolysis, IL-1β, and T Helper Cell Responses to Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is the leading infectious killer in the world. Mycobacterium tuberculosis (Mtb), the bacteria that causes the disease, is phagocytosed by alveolar macrophages (AM) and infiltrating monocyte-derived macrophages (MDM) in the lung. Infected macrophages then upregulate effector functions through epigenetic modifications to make DNA accessible for transcription. The metabolic switch to glycolysis and the production of proinflammatory cytokines are key effector functions, governed by epigenetic changes, that are integral to the ability of the macrophage to mount an effective immune response against Mtb. We hypothesised that suberanilohydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor (HDACi), can modulate epigenetic changes upstream of the metabolic switch and support immune responses during Mtb infection. The rate of glycolysis in human MDM, infected with Mtb and treated with SAHA, was tracked in real time on the Seahorse XFe24 Analyzer. SAHA promoted glycolysis early in the response to Mtb. This was associated with significantly increased production of IL-1β and significantly reduced IL-10 in human MDM and AM. Since innate immune function directs downstream adaptive immune responses, we used SAHA-treated Mtb-infected AM or MDM in a co-culture system to stimulate T cells. Mtb-infected macrophages that had previously been treated with SAHA promoted IFN-γ, GM-CSF, and TNF co-production in responding T helper cells but did not affect cytotoxic T cells. These results indicate that SAHA promoted the early switch to glycolysis, increased IL-1β, and reduced IL-10 production in human macrophages infected with Mtb. Moreover, the elevated proinflammatory function of SAHA-treated macrophages resulted in enhanced T helper cell cytokine polyfunctionality. These data provide an in vitro proof-of-concept for the use of HDACi to modulate human immunometabolic processes in macrophages to promote innate and subsequent adaptive proinflammatory responses.

The Warburg Effect Occurs Rapidly in Stimulated Human Adult but Not Umbilical Cord Blood Derived Macrophages

“…Newborn babies are more susceptible than adults to a variety of bacterial infections, including from gram negative organisms (containing LPS) and from intracellular pathogens such as Mycobacterium tuberculosis (Mtb) (15,16), the causative agent of Tuberculosis (TB). Our laboratory has previously shown that adult human macrophages shift their metabolic function toward aerobic glycolysis after Mtb infection (17)(18)(19), a finding replicated in other centres (20,21). Furthermore, research examining monocytes and MDM from umbilical cord blood have shown them to be functionally impaired in relation to adult comparators, although the data can be contradictory (22)(23)(24).…”

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

“…This process, also termed the “Warburg Effect”, involves a shift in cellular energy metabolism to increased glycolysis and reduced oxidative phosphorylation, thereby causing TCA cycle intermediates to accumulate (25). Indeed, in vitro studies of human pulmonary macrophages show the ability of Mtb to induce aerobic glycolysis is necessary to stimulate production of IL-1β (23, 26).…”

The Emerging Role of Epigenetic Mechanisms in the Causation of Aberrant MMP Activity during Human Pathologies and the Use of Medicinal Drugs

“…Elucidating the epigenetic mechanisms involved in chronic diseases and infections can be critical not only to understand the pathogenesis mechanisms of these diseases but also to design novel therapeutic interventions. For instance, in tuberculosis, the inhibition of HDACs using suberanilohydroxamic acid (SAHA), also known as the drug Vorinostat, resulted in an immune response by macrophages and subsequently T cells against Mtb [ 86 ]. This immune response involved increased production of IL-1β and reduction of IL-10, accompanied by stimulation of T cells in a human Mtb-infected macrophage culture system [ 86 ].…”

“…For instance, in tuberculosis, the inhibition of HDACs using suberanilohydroxamic acid (SAHA), also known as the drug Vorinostat, resulted in an immune response by macrophages and subsequently T cells against Mtb [ 86 ]. This immune response involved increased production of IL-1β and reduction of IL-10, accompanied by stimulation of T cells in a human Mtb-infected macrophage culture system [ 86 ]. Furthermore, in water-borne parasitic infections by Cryptosporidium species (causing cryptosporidiosis) such as C. parvum, Vorinostat showed anti-parasitic in vitro and in vivo potential by targeting the HDAC of C. parvum [ 87 ].…”