GPR161 contributes to macrophage glycolytic reprogramming via targeting C5aR1 in acute lung injury

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory disorders characterized by a dysregulated and excessive inflammatory response within the pulmonary system. Recent studies have underscored the pivotal role of macrophage activation in driving inflammatory processes, with glycolytic reprogramming emerging as a critical regulator of macrophage function. In this study, we observed significantly elevated expression levels of G protein-coupled receptor 161 (GPR161) in peripheral circulating monocytes from patients with ARDS, with GPR161 expression positively correlating with disease severity. Utilizing genetically engineered mouse models, including global and macrophage-specific conditional knockout mice, we demonstrated that GPR161 deficiency attenuated pulmonary inflammatory damage in lipopolysaccharide-induced and sepsis-associated ALI mice. In vitro experiments further elucidated the essential role of GPR161 in macrophage activation and glycolytic reprogramming. Mechanistic investigations, integrating RNA sequencing with co-immunoprecipitation and surface plasmon resonance assays, identified complement component 5a receptor 1 (C5aR1) as a downstream target of GPR161 and showed that GPR161 promotes glycolytic reprogramming in macrophages by suppressing C5aR1 expression. Collectively, these findings demonstrate that GPR161 enhances macrophage activation and glycolytic reprogramming in ALI/ARDS through a C5aR1-dependent mechanism. These results establish macrophage GPR161 as a promising therapeutic target for the treatment of ALI/ARDS.