GPR84 and Neuroinflammation: A Receptor Worth Targeting, or A Target Worth Reconsidering?

Area of Science:

• Immunology
• Neuroscience
• Pharmacology

Background:

• GPR84 is a G-protein-coupled receptor expressed on innate immune cells, upregulated by inflammation.
• It activates pro-inflammatory pathways (MAPK/ERK, NF-κB, NLRP3 inflammasome) in myeloid cells.
• Microglial GPR84 is linked to neuroinflammation, but its role is context-dependent.

Purpose of the Study:

• To review the complex, context-dependent roles of GPR84 in innate immunity and disease.
• To analyze the reasons for translational failures of GPR84-targeting drugs.
• To propose future research directions for evaluating GPR84's therapeutic potential.

Main Methods:

• Review of existing literature on GPR84 function, preclinical studies, and clinical trials.
• Analysis of G-protein-biased agonists and antagonists.
• Discussion of methodological limitations in current research.

Main Results:

• GPR84 exhibits context-dependent pro- and anti-inflammatory roles, varying by cell type and disease stage.
• Clinical trials of GPR84 antagonist GLPG1205 failed, suggesting issues with preclinical models and drug development.
• Conflicting preclinical data arise from methodological limitations like supraphysiological concentrations and constitutive knockouts.

Conclusions:

• GPR84's therapeutic potential is currently unclear due to conflicting evidence and translational failures.
• Methodological limitations in preclinical research impede accurate assessment of GPR84's role.
• Future research requires conditional models, CNS-penetrant tools, and multiomics to resolve GPR84's complex biology and therapeutic utility.