ALX/FPR2 Contributes to Serum Amyloid A-Induced Lung Neutrophil Recruitment Following Acute Ozone Exposure

Ozone (O₃) is a toxic air pollutant that causes pulmonary inflammation, neutrophil recruitment, and lung injury. Part of the inflammatory response to O₃ includes altered expression of formyl peptide receptor 2 (ALX/FPR2), a G protein-coupled receptor expressed primarily in immune cells. ALX/FPR2 is considered either anti-inflammatory/proresolving or proinflammatory depending on its ligands, which include lipoxin A4 or serum amyloid A (SAA). While the anti-inflammatory/proresolving lipoxin A4 ligand has been well studied, there remains a significant knowledge gap in the interaction between proinflammatory SAA and ALX/FPR2. To date, SAA has been shown to increase neutrophil recruitment through ALX/FPR2 and is increased systemically after O₃ exposure. However, it is unclear if pulmonary SAA signals through ALX/FPR2 during the O₃-induced inflammatory response. We hypothesized that ALX/FPR2-SAA signaling is required to initiate neutrophil recruitment to the lungs following O₃ exposure. To test this hypothesis, ALX/FPR2 wild type (FPR2^+/+) or knockout (FPR2^-/-) mice were exposed to filtered air (FA) or 1 ppm O₃ for 3 h. Pulmonary inflammation was assessed 6, 24, and 48 h following O₃ exposure. FPR2^-/- mice exhibited impaired neutrophil recruitment at 6 and 24 h after O₃ exposure. In addition, FPR2^-/- mouse pulmonary SAA expression was significantly increased after O₃ exposure compared to FPR2^+/+ mice. FPR2^+/+ mice dosed with SAA via oropharyngeal aspiration had increased pulmonary neutrophils, while neutrophils were not increased in FPR2^-/- mice. Taken together, these data indicate that ALX/FPR2 may contribute to SAA-induced pulmonary neutrophilia following O₃ exposure.