Targeting GPR84 to alleviate acute immune-mediated liver injury.

Abstract

Background: GPR84 is a Gi-coupled G-protein-coupled receptor (GPCR) predominantly expressed in immune cells, with its expression upregulated during inflammatory conditions. However, its specific role in immune-mediated liver injury remains unclear.

Methods: We utilized a concanavalin A (Con A)-induced mouse model to simulate immune-mediated liver injury. The expression of GPR84 was assessed by quantitative RT-PCR and western blotting. GPR84 gene knockout mice were employed to evaluate the receptor's functional role. Bone marrow chimeric mice were created to determine the involvement of hematopoietic cells. Infiltrating liver inflammatory cells were analyzed by flow cytometry. The activation of key signaling pathways in hepatic tissues was assessed by western blotting. The GPR84 antagonist GLPG1205 was tested in this model to evaluate its therapeutic potential.

Results: GPR84 expression was significantly upregulated in the mouse liver following Con A injection. Mice lacking GPR84 exhibited reduced serum ALT and AST levels, diminished liver damage, and decreased apoptosis. Additionally, the expression levels of inflammatory cytokines MCP-1 and TNF-α were significantly lower in Gpr84^-/- mice compared to wild-type (WT) mice after Con A injection. Flow cytometry analysis revealed a notable reduction in the proportion of Kupffer cells and infiltrating monocytes (CD11b⁺Ly6C^lowLy6G⁻) in Gpr84^-/- mice. Using bone marrow chimeric mice, we demonstrated that GPR84-deficient bone marrow-derived cells mitigate Con A-induced liver injury. Furthermore, GPR84 deficiency was associated with reduced hepatic apoptosis and lower phosphorylation levels of STAT3, ERK, JNK, p38, and p65, effectively inhibiting key inflammatory signaling pathways. Importantly, treatment with the GPR84 antagonist GLPG1205 significantly lowered serum ALT and AST levels, reduced the expression of inflammatory cytokines, and alleviated liver damage.

Conclusions: Our findings suggest that GPR84 plays a pivotal role in immune-mediated liver injury, primarily through its expression on hematopoietic cells. Targeting GPR84, particularly with the antagonist GLPG1205, offers a promising therapeutic strategy for treating immune-related liver diseases.