Enhanced Proinflammatory Cytokine Production and Immunometabolic Impairment of NK Cells Exposed to Mycobacterium tuberculosis and Cigarette Smoke.

Yafei Rao,Yanqing Le,Xueyang Zhang,Jing Xiong,Xiaoyan Gai,Yujia Liu,Yongchang Sun,Jundong Wang,Wenli Cao

doi:10.3389/fcimb.2021.799276

Abstract

AimSmoker COPD patients with chest radiological signs of prior tuberculosis (TB) showed more severe lung damage, but the mechanisms remain unclear. Emerging evidence has implicated NK cells in the pathogenesis of both COPD and TB. The purpose of this study was to delineate the profile and cytokine production of NK-cell subpopulations and their immunometabolic changes after exposure to both cigarette smoke (CS) and Mycobacterium tuberculosis(MTB).MethodsWe profiled NK-cell subpopulations in terms of percentage and cytokine production by flow cytometry in smoker patients with pulmonary TB (PTB). In an in vitro coexposure model, we investigated proinflammatory cytokine production, glycolytic influx, and oxidative phosphorylation of NK cells under CS extract (CSE) and PPD costimulation.ResultsPeripheral blood NK cells in smoker patients with active PTB (CS+PTB group) showed altered proportion of subpopulations and excessive proinflammatory cytokine expressions. In vitro, CSE- and PPD-coexposed NK-92 cells displayed enhanced proinflammatory cytokine production, concurrent with decreased glycolytic influx and oxidative phosphorylation.ConclusionSmoker patients with active PTB showed enhanced proinflammatory cytokine expression within altered NK cell subpopulations. CSE and PPD coexposure induced heightened cytokine production concurrent with impaired cell metabolism in NK cells. These novel data suggest a potential role of NK cells in the pathogenesis of lung injury in subjects with coexposure to CS and TB.

Highlights

Chronic obstructive pulmonary disease (COPD) is a common chronic airway disease, which is characterized by persistent airway inflammation, lung tissue destruction, and small airway fibrosis (Singh et al, 2019)
The frequency of CD16−CD56bright NK cells was higher in Cigarette smoke (CS)+ PTB group as compared with the healthy nonsmokers (HNS) and PTB groups, suggesting that CS exposure drove the increase in the CD16−CD56bright NKcell subpopulation (Figure 1B)
We found that NK-92 cells in the CS extracts (CSE)- and purified protein derivative tuberculin (PPD)-coexposed group and in the PPD group, but not in the CSE group, showed decreased lactate production (Figure 4G), indicating that PPD but not CSE decreased cell glycolysis

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a common chronic airway disease, which is characterized by persistent airway inflammation, lung tissue destruction (emphysema), and small airway fibrosis (Singh et al, 2019). TBassociated COPD is gaining more attention as a unique phenotype, which is probably associated with persistent lung injury despite microbiological cure (Siddharthan et al, 2020). Our previous study showed that COPD patients (mostly smokers) with chest CT signs of prior tuberculosis had more severe emphysema and a higher prevalence of bronchiectasis, suggesting exaggerated lung injury in subjects with coexposure to CS and TB (Jin et al, 2018). The cellular and molecular mechanisms underlying lung injury in subjects with coexposure to CS and TB have been rarely studied

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