Functional and metabolic impairment in cigarette smoke-exposed macrophages is tied to oxidative stress

Abstract

Cigarette smoke inhalation exposes the respiratory system to thousands of potentially toxic substances and causes chronic obstructive pulmonary disease (COPD). COPD is characterized by cycles of inflammation and infection with a dysregulated immune response contributing to disease progression. While smoking cessation can slow the damage in COPD, lung immunity remains impaired. Alveolar macrophages (AMΦ) are innate immune cells strategically poised at the interface between lungs, respiratory pathogens, and environmental toxins including cigarette smoke. We studied the effects of cigarette smoke on model THP-1 and peripheral blood monocyte derived macrophages, and discovered a marked inhibition of bacterial phagocytosis which was replicated in primary human AMΦ. Cigarette smoke decreased AMΦ cystic fibrosis transmembrane conductance regulator (CFTR) expression, previously shown to be integral to phagocytosis. In contrast to cystic fibrosis macrophages, smoke-exposed THP-1 and AMΦ failed to augment phagocytosis in the presence of CFTR modulators. Cigarette smoke also inhibited THP-1 and AMΦ mitochondrial respiration while inducing glycolysis and reactive oxygen species. These effects were mitigated by the free radical scavenger N-acetylcysteine, which also reverted phagocytosis to baseline levels. Collectively these results implicate metabolic dysfunction as a key factor in the toxicity of cigarette smoke to AMΦ, and illuminate avenues of potential intervention.

Metabolic reprogramming: A driver of cigarette smoke-induced inflammatory lung diseases

“…In addition to ROS production, CSE exposure inhibited oxidative phosphorylation with a compensatory increase of glycolysis, suggesting a shift of metabolism in AMs [29]. The CSE-induced phagocytosis defect could be replicated by hydrogen peroxide treatment, and N-acetyl cysteine both decreased CSE-induced glycolysis and reversed the effect of CSE and hydrogen peroxide on phagocytosis [29]. This interplay between CSE-induced metabolic alteration and ROS generation indicates the potential attribution of metabolic dysregulation during pulmonary pathogenesis.…”

“…However, treating the macrophages with N-acetyl cysteine, a free radical scavenger, could restore the phagocytic function of those ECVC-exposed macrophages [28]. A recent report has observed the downregulation of phagocytosis of AMs is due to cigarette smoke extract (CSE)-induced glycolysis and ROS generation [29]. In addition to ROS production, CSE exposure inhibited oxidative phosphorylation with a compensatory increase of glycolysis, suggesting a shift of metabolism in AMs [29].…”

“…A recent report has observed the downregulation of phagocytosis of AMs is due to cigarette smoke extract (CSE)-induced glycolysis and ROS generation [29]. In addition to ROS production, CSE exposure inhibited oxidative phosphorylation with a compensatory increase of glycolysis, suggesting a shift of metabolism in AMs [29]. The CSE-induced phagocytosis defect could be replicated by hydrogen peroxide treatment, and N-acetyl cysteine both decreased CSE-induced glycolysis and reversed the effect of CSE and hydrogen peroxide on phagocytosis [29].…”

Understanding and Exploiting the Effect of Tuberculosis Antimicrobials on Host Mitochondrial Function and Bioenergetics

“…Moreover, in addition to the ability of an antimicrobial to mitigate mitochondrial function, and the inherent connectivity of OXPHOS, glycolysis and the TCA cycle, it is feasible that drug-induced alterations in OXPHOS also modulate the activity of the TCA cycle and glycolysis. For example, if an antimicrobial resulted in a decline in ATP levels due to its ability to negatively affect ATP production through OXPHOS, this could result in the upregulation of glycolysis and increased flux through the TCA cycle, to compensate for the deficiency in ATP levels (Cloonan et al, 2016 ; Aridgides et al, 2019 ). Consequently, such increases in glycolysis could also be associated with a more oxidative and pro-inflammatory microenvironment in immune cells (Cloonan et al, 2016 ; Aridgides et al, 2019 ).…”

“…For example, if an antimicrobial resulted in a decline in ATP levels due to its ability to negatively affect ATP production through OXPHOS, this could result in the upregulation of glycolysis and increased flux through the TCA cycle, to compensate for the deficiency in ATP levels (Cloonan et al, 2016 ; Aridgides et al, 2019 ). Consequently, such increases in glycolysis could also be associated with a more oxidative and pro-inflammatory microenvironment in immune cells (Cloonan et al, 2016 ; Aridgides et al, 2019 ). Indeed, LZD-treated THP-1 monocytes stimulated with LPS exhibit increased transcript levels of IL-1β, TNF-α, IL-6, and IL-10 (Bode et al, 2015 ).…”