Dexamethasone Reduces Metabolic Function and Subsequent Activation of Human Macrophages to Mycobacterium tuberculosis.

Title: Dexamethasone Reduces Metabolic Function and Subsequent Activation of Human Macrophages to Mycobacterium tuberculosis.
Author(s): L Thong DJ Cox J Keane
Institution: TTMI, Trinity College Dublin
Poster: Click to view poster
Category: CF and Pulmonary Infections
Abstract: Corticosteroids are ubiquitous in the field of respiratory medicine due to their potent anti-inflammatory and immune-modulating properties. More recently in the COVID-19 pandemic, corticosteroids are one of the only effective treatments for patients with COVID-19, particularly in individuals requiring respiratory support. Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis (TB). Furthermore, the emergence of extreme multidrug resistant Mtb drives the need for improved host-directed therapies. Host-directed therapies aim to improve immune responses of patients rather than classical therapies like antibiotics. The most efficient strategies to achieve new host-directed therapies is by repurposing drugs. At present, corticosteroids, such as dexamethasone, are the only approved adjunctive treatment for Mtb with neurological or cardiological involvement. Despite the clinically proven effect of corticosteroids on TB patient survival, the exact mechanism of action underlying this benefit is poorly understood.

Human alveolar macrophages were purified from bronchoalveolar lavage. MDM were obtained from blood of healthy individuals. Dexamethasone treated human macrophages were infected with Mtb. Macrophages were then assessed for cytokine secretion, metabolic gene expression and metabolic flux at multiple timepoints. Dexamethasone significantly reduced secretion of IL-1β, IL-10 and TNF-α following infection. Reduction was also seen in IL-6 and IL-8. Moreover, dexamethasone reduced the expression of metabolic genes and glycolysis in macrophages.

Our data show that dexamethasone reduces glycolysis in human macrophages in both non-infected and infected cells with Mtb. On top of that, dexamethasone appears to decrease macrophages’ capacity to oxidize fatty acid but increases its’ capacity to utilize glutamine as fuel when other pathways are inhibited. This is effect appears to be only seen in cells infected with Mtb. Dexamethasone also reduces the production of cytokines TNF-α, IL-1β and IL-10 in human cells infected with Mtb.

Further studies are needed to fully understand the possible molecular pathways which dexamethasone targets to alter cellular metabolism.