The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages.
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.
1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany [2].
Mahbubur
M
Rahman
1] Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany [2] [3].
Sajjad
S
Muhammad
1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany [2].
Mahtab A
MA
Khan
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Hui
H
Chen
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Dirk A
DA
Ridder
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Helge
H
Müller-Fielitz
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Barbora
B
Pokorná
Institute for Systemic Inflammation Research, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Tillman
T
Vollbrandt
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Ines
I
Stölting
Institute of Radiotherapy and Nuclear Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Roger
R
Nadrowitz
Department of Pediatrics, University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Jürgen G
JG
Okun
1] Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany [2] Medical Faculty, Goethe University, Frankfurt, Germany.
Stefan
S
Offermanns
1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany [2] DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.
Markus
M
Schwaninger
D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D055423:Diet, Ketogenic; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009525:Niacin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism*
C473652:Hcar2 protein, mouse; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D020155:3-Hydroxybutyric Acid