Epithelium-derived Anti-Microbial Peptides Improve the Function of Macrophages

Chronic obstructive pulmonary disease (COPD) is characterized by emphysema, chronic inflammation and increased bacterial colonization of airways associated with exacerbations. While the number of macrophages is elevated in COPD, their phagocytic capacity is attenuated. Antimicrobial peptides (AMP) are naturally occurring proteins with anti-pathogen and proposed immunomodulatory functions. We hypothesize that the airway epithelium-derived AMPs regulate the function of macrophages in COPD. We stimulated non-COPD and COPD small airway epithelial cells (SAEC) with heat-inactivated non-typeable Haemophilus influenzae (Nthi) in air-liquid-interface cultures. We subjected the secretome from apical and basolateral compartment to mass spectrometry and identified a number of secreted AMPs, differentiating between the site of secretion, but not with the Nthi challenge or disease status. We found, however, that Nthi regulated the mRNA expression of AMPs. We observed upregulation of S100A8 and S100A9 after 3h stimulation in non-COPD- to a higher extent than in COPD-derived SAEC but the difference was leveled out after 24h stimulation. This suggests the delayed response in COPD epithelium. Additionally, we used the supernatants collected from SAECs to stimulate primary human monocyte-derived macrophages (MDM). Supernatants from non-COPD cultures had higher impact on phagocytosis in comparison to COPD after 3h Nthi stimulation, but again after 24h this effect was diminished. We next stimulated MDM with S100A8/A9 and observed significant improvement in phagocytosis. Thus, lung epithelium-derived S100A8/A9 could improve phagocytosis in macrophages and this pathway could be explored for therapeutic utility in COPD.