Severe influenza and COVID-19 are marked by excessive infiltration of myeloid cells into the lungs, contributing to hyperinflammation and cytokine storm–associated pathology. However, the mechanisms regulating this immune dysregulation remain incompletely understood. GPR84, a G protein-coupled receptor for medium-chain fatty acids, is expressed on myeloid cells and has been implicated in inflammatory responses, but its role in viral respiratory infections is unknown.
Here, we investigated the function of GPR84 in murine models of influenza A virus (IAV) and SARS-CoV-2 infection. Gpr84 transcription was upregulated in the lungs following infection with both viruses. Pharmacological inhibition of GPR84 using the antagonist GLPG1205 during IAV infection reduced disease severity, as evidenced by attenuated weight loss and viral replication. GPR84 antagonism also decreased macrophage and neutrophil infiltration while enhancing CD4⁺ T cell recruitment. Gpr84 expression correlated with elevated levels of pro-inflammatory cytokines (e.g., Tnf, Ccl2, Ifnb, Ifng, Ifnl), and GLPG1205 treatment reduced IL-6 and IFNγ levels while enhancing type I and III interferon responses. Similar protective effects were observed in SARS-CoV-2–infected mice, including reduced viral load.
These findings identify GPR84 as a key regulator of myeloid-driven inflammation in viral lung infections and provide preclinical evidence supporting GPR84 antagonism as a potential therapeutic strategy for severe respiratory diseases.