The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

Nat Commun. 2014 May 21;5:3944. doi: 10.1038/ncomms4944.

Abstract

The ketone body β-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2(-/-) mice. We further demonstrate that nicotinic acid, a clinically used HCA2 agonist, reduces infarct size via a HCA2-mediated mechanism, and that noninflammatory Ly-6C(Lo) monocytes and/or macrophages infiltrating the ischemic brain also express HCA2. Using cell ablation and chimeric mice, we demonstrate that HCA2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD2 production by COX1 and the haematopoietic PGD2 synthase. Our data suggest that HCA2 activation by dietary or pharmacological means instructs Ly-6C(Lo) monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / metabolism*
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Diet, Ketogenic*
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Neuroprotective Agents / pharmacology
  • Niacin / pharmacology
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Nicotinic / metabolism*
  • Stroke / metabolism*

Substances

  • Hcar2 protein, mouse
  • Neuroprotective Agents
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Niacin
  • 3-Hydroxybutyric Acid