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.

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort

“…In at least 1 study, exogenous mtDNA given intravascularly to rodents did not increase circulating mtDNA but increased u-mtDNA (26). U-mtDNA may also originate from renal cells, including glomerular or tubular epithelial cells (56), endothelial cells (44), and immune cells (6,12), as well as lung-derived cell sources (5)(6)(7)(8)(9)(10)(11)16) or muscle (65); further mechanistic studies are needed to identify the source of extracellular mtDNA in COPD. Whether u-mtDNA in COPD is a marker of disease or is pathogenic in itself remains to be determined.…”

“…One underlying biological mechanism that may provide insight into COPD pathogenesis and progression is mitochondrial dysfunction, which is consistently observed in cells derived from COPD subjects (5)(6)(7)(8)(9)(10)(11)(12)(13), as well as in experimental COPD models (11,14). Such mitochondrial dysfunction is associated with the leakage of mitochondrial DNA (mtDNA) (15)(16)(17)(18)(19), a mitochondrial derived danger-associated molecular pattern (mtDAMP) (20,21).…”

Developing Novel Host-Based Therapies Targeting Microbicidal Responses in Macrophages and Neutrophils to Combat Bacterial Antimicrobial Resistance

“…This is associated with increased airway bacterial burden (62). This defect is related to cellular oxidative stress (62,81). Nrf2 agonists are in development, which enhance the host cell's anti-oxidant host defenses, and in COPD AM can enhance phagocytosis as well as clearance of P. aeruginosa in mice exposed to cigarette smoke (62,82).…”

ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly

“…An important cellular player regarding mitochondrial dysfunction and lung ageing are macrophages, which display phenotypic changes and defective phagocytosis in COPD [79]. In the intranasal cigarette smoke model, macrophages secreted higher levels of TNF-α and IL-1β and the inflammatory macrophage marker, MARCO, was elevated on the cell surface.…”