IFN-γ and IL-17A differentially influence the response of human macrophages and neutrophils to Pseudomonas aeruginosa infection

Macrophages are important orchestrators of inflammation during bacterial infection acting both as effector cells and as regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct inflammatory and microbicidal potential have been described. Our previous work unveiled a positive and a negative correlation between levels of IFN-γ and IL-17A, respectively, and lung function in cystic fibrosis, particularly in patients chronically infected with P. aeruginosa. This study sought to define key parameters in human anti-bacterial immunity under Th1- and Th17-dominated inflammatory conditions; the final aim was to identify unique characteristics that could be fine-tuned therapeutically to minimise tissue damage while maximising bacterial clearance. Towards this aim neutrophils were incorporated into cultures of macrophages treated with IFN-γ or IL-17A and infected with P. aeruginosa. The intent of this design was to model (i) initiation of inflammation by infected macrophages and (ii) delayed arrival of neutrophils and their exposure to macrophage-derived cytokines. Under these conditions IFN-γ decreased bacterial killing and promoted production of the monocyte chemoattractant MCP-1. In contrast, IL-17A promoted bacterial killing but did not affect MCP-1 production. Secretion of the pyrogen IL-1β was significantly lower in the presence of IFN-γ compared to IL-17A and correlated with levels of IL1B transcript in infected macrophages. These findings support the validity of this model to investigate human anti-bacterial immunity. Based on these observations, the protective and damaging roles of IFN-γ and IL-17A, respectively, during P. aeruginosa infection could be caused by their contrasting effects on IL-1β and MCP-1 production