Nutritional or pharmacological activation of HCA2 ameliorates neuroinflammation

• Beta-hydroxybutyrate, nicotinic acid, and monomethyl fumarate activate HCA2 (GPR109A).
• HCA2 on neutrophils and monocyte-derived cells modulates neuroinflammation.
• HCA2 activation protects against experimental models of neurological diseases.
• New HCA2 agonists are candidates for the therapy of neurological diseases.

Neuroinflammation is a pathology common to many neurological diseases, including multiple sclerosis (MS) and stroke. However, therapeutic attempts to modulate neuroinflammation have proved difficult. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation. Furthermore, we discuss the mechanisms underlying the beneficial effects of HCA2 activation in neuroinflammatory diseases and the therapeutic potential of recently developed synthetic ligands of HCA2.