Effects of cigarette smoke on Toll‐like receptor ( TLR ) activation of chronic obstructive pulmonary disease ( COPD ) macrophages

Summary Chronic obstructive pulmonary disease ( COPD ) is characterized by an abnormal innate immune response. We have investigated the changes in the innate immune response of COPD alveolar macrophages exposed to both cigarette smoke and Toll‐like receptor ( TLR ) stimulation. COPD and control alveolar macrophages were exposed to cigarette smoke extract ( CSE ) followed by TLR‐ 2, ‐4 and ‐5 ligands [ P am3 CSK 4, lipopolysaccharide ( LPS) and phase I flagellin ( FliC), respectively] or non‐typeable H aemophilus influenzae ( NTHi ). CSE exposure suppressed TLR ‐induced tumour necrosis factor ( TNF) ‐α, interleukin ( IL) ‐6, IL ‐10 and regulated on activation, normal T cell expressed and secreted (RANTES) production in both COPD and control alveolar macrophages, but had no effect on interleukin 8 ( CXCL 8) production. Similarly, CSE suppressed NTHi ‐induced TNF ‐α but not NTHi ‐induced CXCL 8 production in COPD alveolar macrophages. Gene expression analysis showed that CSE suppressed LPS ‐induced TNF ‐α transcription but not CXCL 8 transcription in COPD alveolar macrophages. The dampening effect of CSE on LPS ‐induced cytokine production was associated with a reduction in p38, extracellular signal regulated kinase (ERK) and p65 activation. In conclusion, CSE caused a reduced innate immune response in COPD alveolar macrophages, with the exception of persistent CXCL 8 production. This could be a mechanism by which alveolar macrophages promote neutrophil chemotaxis under conditions of oxidative stress and bacterial exposure.