A brief history of GPR84

In 2001 Yousefi, Cooper, et al . (2001) reported the cloning and expression analysis of a transcript identified in human neutrophils. Among other chemokine receptor like genes the authors identified the EX33 gene encoding a 396 amino acid protein. Transcription profiling identified higher levels of EX33 mRNA in neutrophils and eosinophils than B- and T-lymphocytes with high expression in bone marrow and lung. An independent study by Wittenberger, Schaller, et al . (2001) identified 14 expressed sequence tags with homology to GPCRs including GPR84 - identical to the open reading frame of EX33 (Fig 1).
In 2005 the pharmaceutical company Tularik generated the first GPR84-/- knockout mouse and reported a modest phenotype for these animals (Venkataraman & Kuo, 2005).GPR84-/- T- and B- lymphocyte proliferation in response to a range of mitogens was normal but the authors reported that stimulation of T-cells with anti-CD3 antibodies led to increased Interleukin-4 and Interleukin-5 production.GPR84-/- mice showed no difference in antibody response to ovalbumin as an antigen.
In 2006 Wang, Wu, et al . (2006) published the first report of agonists that activated the GPR84 receptor expressed in transfected cells. The authors transfected CHO cells with human or murine GPR84 expression vectors, an aequorin reporter gene and a mixture of G proteins. mGPR84 transfected CHO cells showed Ca2+ responses to the medium chain fatty acids (MCFAs) capric acid (C10; Fig 2), undecanoic acid (C11), and lauric acid (C12). Similar results were obtained using stably transfected CHO cells using cAMP inhibition assays and [35S]GTPγS assays that could be blocked by treatment with pertussis toxin. Importantly the same paper reported significant Gpr84 expression in human and murine macrophages and that the identified MCFA ligands enhanced secretion of IL-12 p40 expression in the murine RAW macrophage cell line treated with LPS. Wang, Wu, et al . (2006) also described diindolylmethane (DIM; Fig 2) as a surrogate agonist for GPR84.
In 2013 Suzuki, Takaishi, et al . (2013) reported a synthetic GPR84 agonist 6-n-octylaminouracil (6-OAU; Fig 2). The authors showed that 6-OAU elicited human neutrophil and macrophage chemotaxis and amplified the production of the pro-inflammatory cytokine TNFα from LPS treated macrophages. Further evidence for the pro-inflammatory effects of GPR84 agonists came from recruitment of polymorphonuclear leukocyte and macrophages following injection of 6-OAU into a rat dorsal air pouch.
In 2015 it was reported thatGPR84-/- mice did not develop mechanical or thermal hypersensitivity following sciatic nerve ligation, a phenotype the authors attributed to reduced pro-inflammatory effects inGPR84-/- macrophages (Nicol, Dawes et al. , 2015). In the same year Audoy-Remus, Bozoyan, et al . (2015) showed that GPR84-/- crossed with the APP/PS1 mouse model of Alzheimer’s Disease showed greater dendritic degeneration and cognitive decline compared to wild-type mice. The authors saw no difference between GPR84-/- and wild-type mice in endotoxaemia or the experimental autoimmune encephalomyelitis model of multiple sclerosis. The GPR84 antagonist GLPG1205 failed to meet efficacy endpoints in a PhII clinical trial for ulcerative colitis (Vermeire, Reinisch et al. , 2017) (NCT02337608).
In 2016 Zhang, Yang, et al . (2016) used HEK cells transfected with hGPR84 and Gα16 to screen a library of 160,000 small molecules and identified the potent GPR84 agonist, ZQ-16, also known as 2-HTP (Fig 2). Liu, Zhang, et al . (2016) identified the most potent agonist of the time, LY-237, also known as cpd 51 (Fig 2).
In 2017 PBI-4050 failed to meet efficacy endpoints in the treatment of idiopathic pulmonary fibrosis (Khalil, Manganas et al. , 2019) (NCT02538536).
In 2018 Gaidarov, Anthony et al . (2018) identified the natural product embelin (Fig 2) as a potent GPR84 agonist and synthesised and tested other dihydroxybenzoquinone analogues with varying alkyl tail chain lengths. The authors reported that GPR84 activation drives human neutrophil chemotaxis and primes amplification of oxidative burst while implicating macrophage GPR84 activation with reverse cholesterol transport in macrophage foam cells. In the same year Recio, Lucy, et al . (2018) reported that the GPR84 agonist 6-OAU augmented macrophage inflammatory responses and enhanced macrophage phagocytosis. Activation of GPR84 was also shown to trigger ROS release from TNFα or Latrunculin-A primed neutrophils (Sundqvist, Christensonet al. , 2018).
In 2019 Lucy, Purvis et al . (2019) reported a novel biased agonist DL-175 (Fig 2) that was active in the Gαipathway but inactive in the β-arrestin pathway. Dietary supplementation with lauric acid, perilla oil, and DIM together, which target both GPR84 and FFAR4 and were formulated using colonic release capsules, was found to reduce energy intake in obese adults (Peiris, Aktar et al. , 2022) (NCT04292236).
In 2020 GPR84 antagonist GLPG1205 failed to meet primary endpoint outcomes for the treatment of idiopathic pulmonary fibrosis (Strambu, Seemayer et al. , 2023) (NCT03725852). Kӧse, Pillaiyar,et al . (2020) reported an agonist radioligand, [3H]PSB-1584, which was used to measure the binding affinities of other agonists, including DIM which is shown to allosterically increase the specific binding of [3H]PSB-1584.
In 2022 Marsango, Ward, et al . (2022) identified key residues in the intracellular loop 3 of GPR84 which undergo GRK2/3-mediated phosphorylation in an agonist-dependent manner, revealing a step in the mechanism underlying the β-arrestin bias of DL-175.