Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

Abstract

Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD.Monocyte-derived macrophages (MDMs) were generated from non-smoker, smoker and COPD subjects, differentiated in either granulocyte macrophage-colony stimulating factor (G-Mφ) or macrophage-colony stimulating factor (M-Mφ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage fluid. Macrophages were incubated in ±200 µM H2O2 for 24 h, then exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, after which phagocytosis, mitochondrial ROS (mROS) and mitochondrial membrane potential (ΔΨm) were measured.Phagocytosis of bacteria was significantly decreased in both G-Mφ and M-Mφ from COPD patients compared with from non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or ΔΨm; however, in COPD, phagocytosis increased early mROS and decreased ΔΨm in both G-Mφ and M-Mφ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages and non-smoker MDMs, associated with reduced mROS production.COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.

Conflict of interest statement

Conflict of interest: K.B.R. Belchamber reports grants from MRC during the conduct of the study. Conflict of interest: R. Singh has nothing to disclose. Conflict of interest: C.M. Batista reports grants from the National Institute for Health Research during the conduct of the study; and reports grants from Cempra Pharmaceuticals, lecture fees and educational presentations, outside the submitted work. Conflict of interest: M.K. Whyte reports grants from MRC during the conduct of the study; and reports grants for travel from Boehringer Ingelheim, outside the submitted work. Conflict of interest: D.H. Dockrell reports grants from MRC and Wellcome Trust during the conduct of the study; and grants from GSK, advisory board membership for Lilly and ViiV, non-financial support from Novartis, and other funding from AstraZeneca, MedImmune, RedX Pharmaceuticals, Sygnature Discovery, Pfizer and GSK, outside the submitted work. Conflict of interest: I. Kilty is an employee of Pfizer and holds stocks in Pfizer. Conflict of interest: M.J. Robinson is an employee of MedImmune and holds stocks in MedImmune. Conflict of interest: J.A. Wedzicha reports grants from GSK and Johnson and Johnson, other funding from Novartis, Boehringer Ingelheim, AstraZeneca and GSK, and grants from GSK, AstraZeneca, Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: P.J. Barnes has nothing to disclose. Conflict of interest: L.E. Donnelly reports grants from MRC during the conduct of the study; and has grants pending from Cempra Inc., AstraZeneca and Boehringer Ingelheim, outside the submitted work.

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