Conclusions and Future Vision

Since its discovery, GPR84 has undergone a large growth in research activity and clinical trials. While the physiological agonist remains elusive, experiments using potent surrogate agonists from multiple chemical classes demonstrate that GPR84 activation on innate immune cells is pro-inflammatory and results in the activation of cell effector functions. While the physiological context also remains unknown, experiments to date indicate that GPR84 agonists augment inflammation by promoting the mobilisation of inflammatory mediators, stimulating migration and chemotaxis, and enhancing phagocytosis. However, the influence of biased signalling on these responses remains unclear. Further utilisation of recently developed biased and allosteric agonists may help to shed light on this question. In addition, we have highlighted that GPR84 seems to be inherently poorly coupled to the β-arrestin pathway. Most surrogate agonists reported to date exhibit a G-protein bias, and there is a trend towards higher G-protein bias with higher potency agonists. Following receptor desensitisation, either directly using functional assays or potentially by following the phosphorylation of recently identified residues on GPR84, could therefore be an important readout when characterising agonist activity in primary immune cells.