Interferon-β regulates proresolving lipids to promote the resolution of acute airway inflammation

Aberrant immune responses, including hyperresponsiveness to Toll-like receptor (TLR) ligands, underlie acute respiratory distress syndrome (ARDS). Type I interferons confer antiviral activities and could also regulate the inflammatory response, whereas little is known about their actions to resolve aberrant inflammation. Here we report that interferon-beta (IFN-beta) exerts partially overlapping, but also cooperative actions with aspirin-triggered 15-epi-lipoxin A(4) (15-epi-LXA(4)) and 17-epi-resolvin D1 to counter TLR9-generated cues to regulate neutrophil apoptosis and phagocytosis in human neutrophils. In mice, TLR9 activation impairs bacterial clearance, prolongs Escherichia coli-evoked lung injury, and suppresses production of IFN-beta and the proresolving lipid mediators 15-epi-LXA(4) and resolvin D1 (RvD1) in the lung. Neutralization of endogenous IFN-beta delays pulmonary clearance of E. coli and aggravates mucosal injury. Conversely, treatment of mice with IFN-beta accelerates clearance of bacteria, restores neutrophil phagocytosis, promotes neutrophil apoptosis and efferocytosis, and accelerates resolution of airway inflammation with concomitant increases in 15-epi-LXA(4) and RvD1 production in the lungs. Pharmacological blockade of the lipoxin receptor ALX/FPR2 partially prevents IFN-beta-mediated resolution. These findings point to a pivotal role of IFN-beta in orchestrating timely resolution of neutrophil and TLR9 activation-driven airway inflammation and uncover an IFN-beta-initiated resolution program, activation of an ALX/FPR2-centered, proresolving lipids-mediated circuit, for ARDS.