Molecular Signaling and Biased Agonism of the CHEMR23 Receptor: Implications for Inflammation Resolution and Bone Remodeling

The chemerin chemokine-like receptor 1 (CHEMR23), a member of the G proteincoupled receptor (GPCR) family, has emerged as a key regulator of immune homeostasis and skeletal remodeling. Notably, CHEMR23 exhibits ligand-specific biased agonism, enabling divergent intracellular signaling pathways depending on the ligand involved. Pro-inflammatory ligands such as chemerin predominantly activate Gi/o protein–dependent cascades, promoting cytokine release, osteoclastogenesis, and tissue degradation. In contrast, the binding of specialized proresolving mediators (SPMs), such as resolvins, preferentially triggers β-arrestin–mediated signaling. This pathway suppresses NF-κB activation, promotes macrophage polarization toward a proresolving phenotype, and facilitates the resolution of inflammation. This signaling bifurcation is particularly relevant in chronic inflammatory diseases characterized by progressive bone loss, including periodontitis. Expression of CHEMR23 is dynamically modulated by inflammatory stimuli, metabolic stress, and genetic polymorphisms, underscoring its potential as a target for resolution- directed therapies. Emerging therapeutic strategies, ranging from lipid-derived SPMs to monoclonal antibodies, are under investigation for their ability to modulate CHEMR23 activity in a ligand- and context-specific manner. This review provides an integrated overview of molecular, cellular, and translational data on CHEMR23, emphasizing its dual functional roles and therapeutic potential in inflammation-associated pathologies.