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.