Relationship of macrophage function and phenotype in COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with elevated inflammatory signals, protease activity and reduced clearance of pathogens. Macrophages are key in driving inflammatory signals that are subsequently followed by resolution of inflammation and return to steady state. In pathologies such as COPD, macrophages may drive development and progression of disease by loss of regulation of inflammatory signals, which, in turn, may be due to changes in phenotype and loss of cell plasticity. This thesis investigated the ability of macrophages to adapt to changes in microenvironment and establish whether cell plasticity is lost in COPD cells leading to a ‘fixed’ inflammatory state. Monocyte-derived macrophages (MDM) and human lung tissue macrophages were cultured in either GM-CSF (pro-inflammatory) or M-CSF (resolving) to evaluate the effect on cell phenotype, function and plasticity between non-smokers, smokers and COPD patients, with the hypothesis that COPD cells would remain inflammatory regardless of environment. COPD cells released higher levels of pro-inflammatory cytokines following LPS stimulation compared to control cells, and this could be further enhanced when cultured in GM-CSF compared to M-CSF. Non-smoker and smoker cells could be driven to become less inflammatory in the presence of M-CSF, while COPD cells could not. COPD cells also demonstrated elevated protease activity and defects in phagocytosis compared to controls, but these were not affected by growth factors. Analysis of macrophage subsets based on cell density highlighted morphological and functional differences in both MDM and tissue macrophages, suggesting that phenotype may be predetermined in monocytes, and not purely influenced by environment. Furthermore, macrophage phenotype in COPD may be influenced by epigenetic modifications, driving changes in gene expression and cell function. KLF4 and CSF1R, which have a role in dampening inflammatory response, were downregulated in COPD and may be one mechanism driving inflammation. COPD macrophages show several defects compared to smokers and non-smokers, in both MDM and tissue macrophages, and demonstrated unilateral plasticity to become more inflammatory. Targeting these processes may therefore allow development of novel anti-inflammatory therapies for this disease.