How GPR84 Senses And Potentiates Inflammation

G-Protein-Coupled Receptor 84 (GPR84)

GPR84 is an inflammation sensor that plays a role in endotoxemia, brain injuries, and obesity.

In this post, we will discuss how to regulate GPR84's function. 

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Basics Of GPR84

 
 https://www.ncbi.nlm.nih.gov/pubmed/29471103

https://www.ncbi.nlm.nih.gov/pubmed/29471103

 

G-Protein-Coupled Receptor 84 (GPR84, aka EX33) is a rhodopsin-like orphan G-protein coupled receptor (GPCR)/seven-transmembrane (7TMR), expressed on monocytes, macrophages and neutrophils as well as hematopoietic tissue, such as bone marrow and peripheral leukocytes. R R

GPR84 is also expressed in brain, heart, muscle, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, and leukocytes. R

It is significantly up-regulated by inflammatory stimuli and can help sense infections. R R

GPR84 itself does not cause inflammation, but can exacerbate it. R

Normally, GPR84 expression is low, but it can be remarkably increased in monocytes/macrophages upon activation by Lipopolysaccharide (LPS). R

High Expression Of GPR84

Similar to other GPCR's it regulates many responses in the body and can sense infections:

  • Aging (in brain) R
  • Diabetes R
  • EAE (in microglia) R
  • High Fat Diet R
  • Infections (bacterial, viral, etc - eg Bordetella pertussis, Staphylococcal enterotoxin B) R R R
  • Inflammation (in general ) - Proinflamamtory cytokines induce GPR84
  • Japanese Encephalitis Virus Infection R
  • LPS/Endotoxemia R
  • Neuropathic Pain R
  • Obesity R
  • Traumatic Brain Injuries R
  • Western Diet - GPR84 expression was increased by 49.9 times in M1 type macrophages isolated from aortic atherosclerotic lesions of LDLR -/-  and NRF2 -/- mice were fed a western diet R

How GPR84 Works

Immune System

GPR84 functions as a proinflammatory receptor in immune cells and acts as a chemoattractant. R

This means it amplifies proinflammatory responses. R

TechnicalLPS stimulation to macrophages up-regulates GPR84 expression, which allows cells to easily respond to the ligands, while GPR84 downregulates expression of TNF mRNA in tolerant human monocytes. R.

For example, GPR84 does not cause Reactive Oxygen Species (ROS) itself, but it is involved in priming of neutrophils for oxidative burst initiated by other proinflammatory agents (e.g. FMLP and C5A). R

Therefore, exacerbates a TH1 immune response, while suppressing a TH2 anti-inflammatory immune response. 

Obesity And Diabetes 

 
 https://www.ncbi.nlm.nih.gov/pubmed/28446062

https://www.ncbi.nlm.nih.gov/pubmed/28446062

 

GPR84 mediates the involvement of medium-chain FFAs in the inflammatory processes provoked by the immune system. R

GPR84 is one possible mechanism by which Medium Chain Triglycerides (MCTs) can exacerbate inflammation. R

Normally a MCT-rich diet can increase plasma Adiponectin levels (which has anti-inflammatory actions), but when GPR84 become overactive (from inflammation) MCFAs may down-regulate adiponectin mRNA expression level. R

To be more specific, by activating GPR84, MCFAs can amplify LPS-stimulated production of the proinflammatory cytokines (e.g. IL-12 p40). R

For example, in response to TNFa-induced inflammation, GPR84 macrophages in adipocytes (fat cells) can exacerbate obesity and diabetes. R

Inflammation-induced GPR84 activation exacerbates insulin resistance, decreases insulin sensitivity and can suppress adiponectin levels. R 

Hunger

GPR84 is expressed in the gastric corpus mucosa and may act as a sensor of food intake. R
 

It also can stimulate the release of peptide hormones including incretins glucagon-like peptide 1 (GLP1) and GLP2. R

Cancer

GPR84 expression may make cancer worse by sustaining β-catenin signaling. R

GPR84 has shown to play a role in:

  • Colon Cancer R
  • Leukemia R
  • Multiple Myeloma R

Neuroinflammation

In the brains of healthy adult mice, very few GPR84-expressing cells are observed. R

GPR84 plays a role in the regulation of microglialinflammatory and neuroinflammatory processes.

  • Alzheimer's Disease - GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment...as loss of GPR84 causes mice to have accelerated cognitive decline and a reduced number of microglia (has no effect on hippocampal neurogenesis). R
  • Endotoxemia - GPR84 stays activated indefinitely from LPS-induced neuroinflammation. R
  • Multiple Sclerosis - GPR84 stays active during models of Experimental Autoimmune Encephalomyelitis (EAE). R
  • TBI - After injury happens to the brain, GPR84 can increase by approximately 47-fold in microglia...fatty acids released from damaged brain cells may act on microglial GPR84 to increase cellular motility R

Pain 

GPR84 contributes to exacerbating inflammation during neuropathic pain. R

Animals deficient in GPR84 have no response to neuronal-damage induced pain (sciatic pain model). R

Kidneys

GPR84 may be a novel biomarker for Systemic Lupus Erythematosus (SLE). R

For example, GPR84 expression is increased in SLE with kidney inflammation vs those without kidney inflammation. R

GPR84 also makes kidney fibrosis worse, although inhibitors (such as PBI-4050) can reverse GPR84 induced fibrosis. R

Reflux

GPR84 may play an important role in the pathogenesis of Gastro-Esophageal Reflux Disease (GERD).

GPR84 is upregulated in esaphogitis and treatment with omeprazole (PPI) or STW5 (a herbal preparation shown to ameliorate esophagitis without affecting pH) was able to reduce lesions of the esophagi and reduce GPR84 expression. R

IBD and Ulcerative Colitis

Suppression of GPR84 expression may be beneficial for Inflammatory Bowel Disease (IBD) by increasing Th2 cytokines (such as increasing IL-4). R R

Anti-TNF therapy in Ulcerative Colitis (UC) patients is able to reduce GPR84 expression and reduce symptoms scores. R

Treatments with GPR84 antagonists have shown to be safe in patients with UC (although effectiveness may not be strong). R

Vascular System

In the vascular system, GPR84 upregulates cholesterol transporters ABCA1 and ABCG1 and stimulates reverse cholesterol transport. R

GPR84 agonists may not initiate the flushing side effects of Niacin and GPR109A while retaining very similar activity on macrophage-mediated anti-atherosclerotic properties. R

Bones

GPR84 overexpression may hinder bone repair (via RANKL suppression). R 

Development

GPR84 may play a role in development. R

For example, Lauric Acid stimulates mammary gland development of pubertal mice (via activation of GPR84 and PI3K/Akt). R

How To Fix GPR84

Reducing inflammation (in general) may help GPR84 expression to act properly. R 

 
 

Ways To Induce GPR84:

  • DIM (strong allosteric activator of GPR84, but doesn't bind to orthosteric site) - 1000 mg of Indole-3-Carbinol (I3C) can peak plasma levels of DIM w/n 2 hours (500–600 ng/ml) which is high enough to partially activate GPR84 directly R R R
  • Embelin (strong agonist to GPR84) R
  • Ghrelin - induces endogenous MCFAs, thus agonizing GPR84 R R
  • Medium chain fatty acids (MCFAs 9-14) - e.g. Decanoic/Capric (C10), Undecanoic (C11) and Lauric (C12) R R
  • ZQ-16 - induces calcium mobilization, inhibits of cAMP accumulation, phosphorylates ERK 1/2, receptor-β-arrestin interaction, and receptor desensitization and internalization R
  • 6-OAU (more potent than diindolylmethane) R R
  • Others → tables in R and more MCFAs below

What Inhibits GPR84:

  • DHA (blocks inflammatory response by GPR84) R
  • Dihydropyrimidinoisoquinolinones R
  • LPG1205 R
  • PBI-4050 R
  • PPIs R
  • STW5 R
 

Full list of MCFAs with affinity to GPR84:

 https://www.ncbi.nlm.nih.gov/pubmed/16966319

https://www.ncbi.nlm.nih.gov/pubmed/16966319

 

Mechanism Of Action

Simple:

  • Increases ABCA1 R
  • Increases ABCG1 R
  • Increases b-Catenin R
  • Increases COX R
  • Increases c-Fos R
  • Increases IL-1b R
  • Increases IL-6 R
  • Increases IL-8 R R
  • Increases IL-12 R
  • Increases KC-GROα R
  • Increases MIP-2 R
  • Increases NGAL R
  • Increases PGE2 R
  • Increases PI3K R
  • Increases Tcf7l2 R
  • Increases TNFa R
  • Increases VEGF R
  • Increases Wnt R
  • Reduces Adiponectin R
  • Reduces cAMP R
  • Reduces IL-4 R
  • Reduces IL-5 R
  • Reduces IL-13 R
  • Reduces RANKL R

Advanced: R

  • R84 initiates Pertussis Toxin (PTX) sensitive Erk1/2 and Akt phosphorylation, PI3K activation, calcium flux, and release of PGE2. 
  • MCFAs actiavte GPR84 at the 2nd extracellular loop (ECL2). R
  • Erk1/2 phosphorylation induced by embelin was completely abrogated in peritoneal macrophages derived from GPR84 deficient mice. 
  • GPR84 activation initiates Gi/o and G12/13 signaling and induces calcium signaling and PI-3 kinase activation.
  • GPR84 signaling in macrophages elicits Gi Gβγ-mediated augmentation of intracellular cAMP, rather than the decrease expected from Giα engagement. 
  • GPR84 activation drives human neutrophil chemotaxis and primes them for amplification of oxidative burst induced by FMLP and C5A. 
  • Loss of GPR84 is associated with attenuated LPS-induced release of proinflammatory mediators IL-6, KC-GROα, VEGF, MIP-2 and NGAL from peritoneal exudates. 
  • GPR84 mediates the release of numerous proinflammatory mediators upon stimulation of pattern recognition receptors such as TLR4, and potentially others. 
  • While initiating numerous proinflammatory activities in macrophages and neutrophils, GPR84 also possesses GPR109A-like antiatherosclerotic properties in macrophages. 
  • Macrophage receptor activation leads to upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulates reverse cholesterol transport. 
  • In fat tissue, GPR84 regulates adiponectin levels. 
  • Knock-out of GPR84 leads to an increase of Th2 cytokines (IL-4, IL-5, IL-13) in mouse CD4+ T lymphocytes.
  • In leukemic stem cells, GPR84 maintains beta-catenin signaling important for acute myeloid leukemia (AML) maintenance.
  • GPR84 activation leads to certain proinflammatory phenotypes. 
  • GPR84 activation increases production of IL-12, a cytokine involved in the Th1/Th2 balance of T helper responses.
  • GPR84 ligands have been shown to induce chemotaxis and stimulate production of IL-8 from PMNs, as well as TNFa from macrophages. 
  • GPR84 knock-out cells exhibited decreased production of several proinflammatory mediators, such as IL-1b, IL-6 and TNFa upon stimulation with lipopolysaccharide.
  • In a neuropathic pain model, loss of GPR84 leads to significantly reduced development of thermal hypersensitivity, possibly due to the absence of GPR84-mediated release of proinflammatory mediators.
  • GPR84 activation reportedly leads to Gi pathway activation, resulting in pertussis toxin sensitive inhibition of cAMP.
  • Many features of GPR84 signaling in macrophages resemble those of GPR109A, a receptor for niacin that is also highly expressed on macrophages.
  • GPR84 activation by embelin indeed leads to Gi and COX mediated PGE2 release, cAMP upregulation, elevation of expression of ABCA1 and ABCG1 cholesterol transporters, and stimulation of reverse cholesterol transport.
  • In cancer, suppression of GPR84 significantly inhibited cell growth by inducing G1-phase cell-cycle arrest in pre-LSCs, reduced LSC frequency, and impaired reconstitution of stem cell-derived mixed-lineage leukemia (MLL) AML, which represents an aggressive and drug-resistant subtype of AML. R R
  • In AD, GPR84 is upregulated in microglia of APP/PS1 transgenic mice. R
  • In bones, GPR84 overexpression blocked RANKL-stimulated phosphorylation of IκBα and three MAPKs, JNK, ERK, and p38, it also reduces NFkb mediated by RANKL. R 

Genetics

GPR84

...unfinished

More Research

  • GPR84 is necessary for proper development of the retina in Xenopus laevis. R