Oxidative stress drives defective efferocytosis in COPD M2-like macrophages

COPD is associated with increased numbers of activated lung macrophages (Mφ) with reduced phagocytic ability and uptake of apoptotic cells (efferocytosis). Mφ may exist as different phenotypes (e.g. M1 pro-inflammatory and M2 anti-inflammatory) but in COPD, Mφ appear to be a distinct phenotype akin to a dysfunctional M2-like cell. This study aimed to examine the effect of oxidative stress on Mφ phenotype in COPD. Monocyte-derived Mφ from non-smokers or COPD subjects were cultured in GM-CSF (G-Mφ, M1-like) or M-CSF (M-Mφ, M2-like) for 12 d (n=4-18). Mφ were exposed to an oxidative stress (200 µM H 2 O 2 for 24 h) and phagocytosis of H.influenzae (HI), S.pneumoniae (SP), or apoptotic neutrophils was measured by flow cytometry. COPD M-Mφ showed increased efferocytosis (63±4 vs 22±3% p<0.005) and phagocytosis (HI 89±3 vs 72±8 p<0.05; SP 87±2 vs 63±8% p<0.01) compared with G-Mφ; with a similar associated increase in the amount of neutrophils (6.4±1 vs 2.6±0.2 MFI p<0.005) and bacteria cleared (SP 15±3.5 vs 8.6±5 MFI p<0.05). Oxidative stress reduced efferocytosis by 31% p<0.005 in M-Mφ from COPD patients, and 2.4 MFI p<0.005, but no effect on G-Mφ. In contrast, oxidative stress did not alter these responses in any Mφ phenotype from non-smokers. Oxidative stress did not alter phagocytosis of either HI or SP by Mφ from any subject group or phenotype. This study suggests that in COPD, M2-like Mφ are sensitive to oxidative stress unlike M1-like Mφ. These data suggest that Mφ phenotype is important in determining responses to oxidative stress in COPD but not in healthy subjects and that altering phenotype might prove a novel therapeutic approach in COPD. Supported by COPD-MAP.