Study finds smoking impairs the bioenergetic immune response to Mtb infection

A recent study aimed to compare baseline metabolic characteristic and the glycolytic response with infection of human AM from smokers and nonsmokers. The researchers obtained AM at bronchoscopy and extracellular flux analyses were conducted to establish baseline metabolic characteristics compared with human monocyte derived macrophages (MDM).

“We hypothesized, therefore, that smokers’ AM would demonstrate an attenuated metabolic response to infection, in line with the attenuated cytokine response observed in these cells. To address this, metabolic interrogation of smokers’ and nonsmokers’ AM was performed using extracellular flux analyses,” the authors wrote. “Our data reveal significant differences in terms of baseline metabolic activity and metabolic reserves, with smokers’ AM ultimately demonstrating an impaired metabolic response to infection that may contribute to increased susceptibility to infection observed in this population.”

Also, differences in glycolytic response were measured by extracellular flux analysis, gene expression analyses, and correlated with production of the glycolysis-driven IL-1β and PGE₂. There were similar tests conducted in cigarette smoke extract (CSE)-treated MDM, representing the alternative model.

The results revealed that at baseline, human AM from nonsmokers typically have a significantly lower extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) ratio than MDM, however, they retain substantial glycolytic reserve. When compared with nonsmokers, smokers’ AM have reduced metabolic activity, reduced glycolytic reserve, and reduced respiratory capacity.

“Human AM demonstrate metabolic plasticity that allows glycolytic reprogramming to occur following Mtb infection,” the authors wrote. “In smokers, this metabolic reserve is significantly attenuated, with consequent impairment of the glycolytic response to infection.”

After infection with Mtb, smokers’ AM were found to have significantly reduced glycolytic response. CSE-treated MDM also demonstrated reduced metabolic activity and reserves, as well as impaired glycolytic response to infection.

“The impact of cigarette smoke on cell metabolism and function is likely broad and complex, but with recent evidence for the critical role of immunometabolism in the innate host defense mechanisms, this work demonstrates fundamental defects in the AM glycolytic response to infection following smoke exposure,” concluded the authors. “As our understanding of this relatively new field grows, host-directed therapies to enhance early glycolytic reprogramming may specifically benefit the smoking population.”

Source: AJMC