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.