Yaeger Michael J, Ngatikaura Tyson, Zecchino Natali, Dunigan-Russell Katelyn, Lovins Hannah B, Schott Evangeline, Hutton Grace, Saunders Brett, Lin Yan, Zhang Junfeng Jim, Cochran Samuel J, Virk Rafia, Cumming R Ian, Hussain Salik, Tighe Robert M, Shaikh Saame Raza, Gowdy Kymberly M
Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Nicholas School of the Environment, Duke University, Durham, North Carolina, USA.
FASEB J. 2025 Jun 15;39(11):e70555. doi: 10.1096/fj.202402865R.
Ozone (O) is a toxic air pollutant that causes pulmonary inflammation, neutrophil recruitment, and lung injury. Part of the inflammatory response to O 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 O exposure. However, it is unclear if pulmonary SAA signals through ALX/FPR2 during the O-induced inflammatory response. We hypothesized that ALX/FPR2-SAA signaling is required to initiate neutrophil recruitment to the lungs following O exposure. To test this hypothesis, ALX/FPR2 wild type (FPR2) or knockout (FPR2) mice were exposed to filtered air (FA) or 1 ppm O for 3 h. Pulmonary inflammation was assessed 6, 24, and 48 h following O exposure. FPR2 mice exhibited impaired neutrophil recruitment at 6 and 24 h after O exposure. In addition, FPR2 mouse pulmonary SAA expression was significantly increased after O 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 O exposure.
臭氧（O）是一种有毒的空气污染物，可导致肺部炎症、中性粒细胞募集和肺损伤。对O的炎症反应部分包括甲酰肽受体2（ALX/FPR2）表达的改变，这是一种主要在免疫细胞中表达的G蛋白偶联受体。根据其配体，ALX/FPR2被认为具有抗炎/促消退或促炎作用，其配体包括脂氧素A4或血清淀粉样蛋白A（SAA）。虽然抗炎/促消退的脂氧素A4配体已得到充分研究，但促炎SAA与ALX/FPR2之间的相互作用仍存在重大知识空白。迄今为止，SAA已被证明可通过ALX/FPR2增加中性粒细胞募集，并且在接触O后全身水平会升高。然而，尚不清楚在O诱导的炎症反应过程中肺部SAA是否通过ALX/FPR2发出信号。我们假设，ALX/FPR2-SAA信号传导是O暴露后启动中性粒细胞向肺部募集所必需的。为了验证这一假设，将ALX/FPR2野生型（FPR2）或敲除（FPR2）小鼠暴露于过滤空气（FA）或1 ppm O中3小时。在O暴露后6、24和48小时评估肺部炎症。FPR2小鼠在O暴露后6和24小时表现出中性粒细胞募集受损。此外，与FPR2小鼠相比，FPR2小鼠在O暴露后肺部SAA表达显著增加。经口咽吸入给予SAA的FPR2小鼠肺部中性粒细胞增加，而FPR2小鼠中性粒细胞未增加。综上所述，这些数据表明，ALX/FPR2可能在O暴露后导致SAA诱导的肺部中性粒细胞增多。
