The b-hydroxybutyrate receptor HCA 2 activates a neuroprotective subset of macrophages

Mahbubur Rahman, Sajjad Muhammad, Mahtab A. Khan, Hui Chen, Dirk A. Ridder, Helge Müller-Fielitz, Barbora Pokorná, Tillman Vollbrandt, Ines Stölting, Roger Nadrowitz, Jürgen G. Okun, Stefan Offermanns, Markus Schwaninger*

*Corresponding author for this work
61 Citations (Scopus)


The ketone body Î 2-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 (HCA 2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 â ̂'/â ̂' mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2. Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

Original languageEnglish
Article number3944
JournalNature Communications
Publication statusPublished - 21.05.2014

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)
  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

  • 204-05 Immunology


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