15-Epi-LXA <sub>4</sub> and 17-epi-RvD1 restore TLR9-mediated impaired neutrophil phagocytosis and accelerate resolution of lung inflammation
Meriem Sekheri, Driss El Kebir, Natalie M. Edner, János G. Filep
Abstract
Significance Timely resolution of bacterial infections critically depends on phagocytosis of invading pathogens by polymorphonuclear neutrophil granulocytes, followed by neutrophil apoptosis and removal by macrophages. Neutrophils integrate cues from the inflammatory microenvironment. Here we show a Toll-like receptor 9-mediated mechanism, involving regulation of phagocytosis and phagocytosis-induced neutrophil apoptosis, by which bacterial DNA, a pathogen-associated molecular pattern, and the danger signal mitochondrial DNA may impair host defense to bacteria and prolong the inflammatory response. We also report that the proresolution aspirin-triggered lipids 15-epi-lipoxin A 4 and 17-epi-resolvin D1 restore impaired phagocytosis and enhance bacterial clearance and phagocytosis-induced neutrophil apoptosis, thereby facilitating resolution of acute lung inflammation. These findings imply the lipoxin receptor ALX/FPR2 as a potential therapeutic target for combating bacterial infections.