Medium-chain Fatty Acid-Sensing Receptor, GPR84, Is a Proinflammatory Receptor

J Biol Chem. 2013 Apr 12;288(15):10684-91. doi: 10.1074/jbc.M112.420042. Epub 2013 Feb 28.

Abstract

G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84. These potential ligands and the surrogate agonist, 6-OAU, stimulated [(35)S]GTP binding and accumulated phosphoinositides in a GPR84-dependent manner. The surrogate agonist, 6-OAU, internalized GPR84-EGFP from the cell surface. Both the potential ligands and 6-OAU elicited chemotaxis of human polymorphonuclear leukocytes (PMNs) and macrophages and amplified LPS-stimulated production of the proinflammatory cytokine IL-8 from PMNs and TNFα from macrophages. Furthermore, the intravenous injection of 6-OAU raised the blood CXCL1 level in rats, and the inoculation of 6-OAU into the rat air pouch accumulated PMNs and macrophages in the site. Our results indicate a proinflammatory role of GPR84, suggesting that the receptor may be a novel target to treat chronic low grade inflammation associated-disease.

MeSH terms

  • Animals
  • CHO Cells
  • Cattle
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism
  • Cricetinae
  • Cricetulus
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics
  • Lipopolysaccharides / toxicity
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Rats
  • Rats, Inbred Lew
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • U937 Cells
  • Uracil / analogs & derivatives
  • Uracil / pharmacology

Substances

  • CXCL1 protein, human
  • CXCL8 protein, human
  • Chemokine CXCL1
  • Cxcl1 protein, rat
  • Fatty Acids
  • GPR84 protein, human
  • Interleukin-8
  • Lipopolysaccharides
  • Receptors, Cell Surface
  • Tumor Necrosis Factor-alpha
  • Uracil