GPR84 aggravates lung inflammation through activating ZBP1-PANoptosome mediated PANoptosis following IAV infection

Influenza virus-induced pneumonia (IVP) is a contagious lung disease marked by severe lung inflammation following viral infection and remains a significant public health concern due to its high mortality rate. G protein-coupled receptor 84 (GPR84) has been implicated in various inflammatory diseases, however, its role in influenza virus-induced lung inflammation remains poorly understood. In this study, using high-throughput screening, we found that Influenza A virus (IAV) infection markedly upregulates the expression of several G protein-coupled receptors, with GPR84 mRNA and protein levels being highly induced in the lungs of animal models during pneumonia. Mechanistically, GPR84 enhances ZBP1-PANoptosome mediated PANoptosis and exacerbates the release of inflammatory chemokines and danger associated molecular patterns (DAMPs). Notably, deletion of GPR84 attenuates influenza virus-induced PANoptosis, indicating that GPR84 participates in regulating lung inflammation and the pathogenesis of pneumonia during influenza infection. Overall, these findings demonstrate that GPR84 plays a central role in influenza virus-induced lung inflammation by promoting PANoptosis and the release of inflammatory mediators. Targeting GPR84 attenuates IAV-induced PANoptosis, highlighting its potential as a therapeutic target to mitigate the pathogenesis of influenza virus-induced pneumonia.