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Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor

Masakatsu Suzuki1, Sachiko Takaishi, Miyuki Nagasaki

  • 1Frontier Research Laboratories, R&D Division, Daiichi Sankyo Company, Limited, Tokyo 140-871, Japan.

The Journal of Biological Chemistry
|March 2, 2013
PubMed

Insights

Researchers identified medium-chain fatty acids (MCFAs) and a novel compound, 6-n-octylaminouracil (6-OAU), that activate G protein-coupled receptor 84 (GPR84). This receptor plays a proinflammatory role, suggesting it as a potential therapeutic target for inflammation-associated diseases.

Area of Science:

  • Biochemistry
  • Immunology
  • Pharmacology

Background:

  • G protein-coupled receptor 84 (GPR84) is a receptor for medium-chain fatty acids (MCFAs) with unclear pathophysiological roles.
  • The function and activation mechanisms of GPR84 remain largely uncharacterized.

Purpose of the Study:

  • To investigate the activation of GPR84 by MCFAs and identify potential agonists.
  • To elucidate the role of GPR84 in inflammatory responses.
  • To explore GPR84 as a potential therapeutic target for inflammation-related diseases.

Main Methods:

  • Activation assays using MCFAs and a novel surrogate agonist, 6-n-octylaminouracil (6-OAU).
  • Measurement of [(35)S]GTP binding and phosphoinositide accumulation.
  • GPR84 internalization studies using GPR84-EGFP.
  • Chemotaxis assays with human polymorphonuclear leukocytes (PMNs) and macrophages.
  • Cytokine production assays (IL-8, TNFα).
  • In vivo studies in rats to assess GPR84 activation and leukocyte recruitment.

Main Results:

  • Hydroxylated MCFAs more effectively activated GPR84 than nonhydroxylated MCFAs.
  • 6-OAU was identified as a potent surrogate agonist for GPR84, inducing receptor-mediated signaling and internalization.
  • Both MCFAs and 6-OAU promoted leukocyte chemotaxis and amplified pro-inflammatory cytokine production.
  • In vivo administration of 6-OAU led to increased CXCL1 levels and leukocyte accumulation in rats.

Conclusions:

  • GPR84 plays a significant proinflammatory role.
  • GPR84 activation by MCFAs and 6-OAU modulates immune cell function.
  • GPR84 represents a promising novel therapeutic target for chronic low-grade inflammation-associated diseases.

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