GPR84 blockade in macrophages mitigates sepsis-induced liver injury via PPARα-driven metabolic reprogramming and M2 polarization.

BACKGROUND & AIMS: Sepsis-associated liver injury (SLI) is a severe complication that substantially worsens clinical outcomes and increases mortality in patients with sepsis, yet its molecular drivers remain poorly defined. Recent meta-analyses identified GPR84, a G protein-coupled receptor activated by saturated medium-chain fatty acids, as markedly upregulated in sepsis, particularly in patients with acute liver injury. This study investigated the functional role of GPR84 in SLI pathogenesis and the mechanisms through which it contributes to disease progression.

APPROACH &

RESULTS

In murine models of SLI, single-cell RNA sequencing and immunohistochemistry revealed that Gpr84 expression is enriched in hepatic macrophages. Both genetic knockdown and pharmacological inhibition of Gpr84 significantly reduced acute liver inflammation. In vitro, Gpr84 blockade suppressed macrophage pro-inflammatory responses and promoted a shift from the M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic profiling linked these protective effects to enhanced lipid metabolic pathways and activation of peroxisome proliferator-activated receptor-α (PPARα). Mechanistically, Gpr84 suppression restored Pparα activity by reactivating the cAMP-PKA-CREB signaling axis. PKA-mediated phosphorylation of Pparα at Ser179 and Thr200 was essential for its activation, while CREB directly bound to and upregulated the Pparα promoter. These coordinated mechanisms improved mitochondrial fatty acid oxidation in macrophages and strengthened their anti-inflammatory capacity. In Pparα-deficient mice, the hepatoprotective effects of Gpr84 inhibition were largely abolished, confirming that Pparα activation is required for therapeutic benefit.

CONCLUSIONS

This study identifies a previously unrecognized GPR84-PPARα regulatory axis as a central driver of SLI and establishes GPR84 as a compelling therapeutic target for mitigating hepatic inflammation in sepsis.