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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-08, Vol.119 (31), p.1-e2201146119
• Main Authors: Sekheri, Meriem, Rizo-Téllez, Salma A., Othman, Amira, El Kebir, Driss, Filep, János G.
• Format: Article
• Language: English
• Subjects: Apoptosis; Aspirin; Biological Sciences; Cell activation; Circuits; E coli; Escherichia coli; Immune clearance; Immune response; Immune system; Inflammation; Inflammatory response; Interferon; Leukocytes (neutrophilic); Lipids; Lipoxin A4; Lungs; Mucosa; Neutralization; Neutrophils; Phagocytosis; Proteins; Respiratory distress syndrome; Respiratory tract; Respiratory tract diseases; TLR9 protein; Toll-like receptors; β-Interferon
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2201146119

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-β (IFN-β) 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-β and the proresolving lipid mediators 15-epi-LXA 4 and resolvin D1 (RvD1) in the lung. Neutralization of endogenous IFN-β delays pulmonary clearance of E. coli and aggravates mucosal injury. Conversely, treatment of mice with IFN-β 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-β–mediated resolution. These findings point to a pivotal role of IFN-β in orchestrating timely resolution of neutrophil and TLR9 activation–driven airway inflammation and uncover an IFN-β–initiated resolution program, activation of an ALX/FPR2-centered, proresolving lipids-mediated circuit, for ARDS.