Reduced expression of the transcription factor KLF4 in COPD macrophages is associated with dysfunctional differentiation

Macrophages (mф) in the lungs of COPD patients show a pro-inflammatory phenotype and fail to clear pathogens and apoptotic cells. Whether this is due to local pulmonary environmental or to an inherent mф defect is not clear. We have shown that monocyte-derived macrophages (MDM) from COPD patients show similar defects, with reduced phagocytosis and increased release of pro-inflammatory cytokines and proteases. Kruppel-like factor (KLF)-4 is a transcription factor that is important in the differentiation of mф. This study aimed to examine whether KLF-4 expression was altered during differentiation of monocytes to mф in COPD. Monocytes from control (C=7) and COPD patients (COPD=5) were cultured in GM-CSF (pro-inflammatory phenotype) or M-CSF (resolving phenotype) for 18d, and <i>KLF4</i> gene expression measured using qPCR. <i>KLF4</i> increased during differentiation from 0d to 12d in both subject groups, but was markedly higher in controls compared to COPD MDM. This was observed in both GM and M cultured cells, although GM-MDM expressed twice as much <i>KLF4</i> than M-MDM. In control cells, <i>KLF4</i> decreased by day 18, but remained the same in COPD MDM (Fig. 1). These data indicate a role for KLF4 in mф differentiation. Furthermore, low gene expression in COPD MDM suggests that these cells are unable to differentiate correctly, or take longer to do so, resulting in dysfunctional mф phenotype.