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

GPR84 is a medium-chain fatty acid (MCFA)-sensing G-protein-coupled receptor conditionally expressed on innate immune cells - neutrophils, monocytes, macrophages, and microglia - with expression strongly induced by inflammatory stimuli. Upon activation, GPR84 engages Gi/o signalling, MAPK/ERK, NF-κB, and NLRP3 inflammasome pathways, amplifying pro-inflammatory effector functions across peripheral and central myeloid populations. In microglia, receptor upregulation marks a disease-associated subpopulation linked to TNF-α and IL-1β production in models of neurodegeneration, traumatic CNS injury, and neuropathic pain. Yet the same receptor exhibits context-dependent protective roles: GPR84 deletion attenuates neuropathic hypersensitivity through peripheral macrophage reprogramming while leaving microglial activation intact, and Gpr84-deficient Alzheimer's disease mice show reduced microgliosis but paradoxically accelerated cognitive decline, demonstrating that the receptor's output is determined by cell type, disease stage, and local inflammatory context rather than by a fixed pro-inflammatory identity. Recent cryo-EM structural resolution of GPR84 has enabled the design of G-protein-biased agonists that preferentially engage pathways linked to motility and phagocytosis while sparing cytokine amplification, providing a rationale for selectively enhancing homeostatic clearance without exacerbating chronic inflammation. However, the most clinically advanced antagonist, GLPG1205, failed to meet primary endpoints in Phase II trials in ulcerative colitis and idiopathic pulmonary fibrosis. This review argues that these translational failures reflect deeper methodological limitations - including supraphysiological agonist concentrations, constitutive knockout models that conflate microglial and peripheral macrophage contributions, species selectivity gaps in available antagonists - that have produced conflicting preclinical evidence and impeded clinical translation. Resolving GPR84's context-dependent biology will require conditional genetic models, CNS-penetrant pharmacological tools, and integration of spatial and temporal multiomics approaches before the receptor's therapeutic potential can be meaningfully evaluated.