Nicotinic acid– and monomethyl fumarate–induced flushing involves GPR109A expressed by keratinocytes and COX-2–dependent prostanoid formation in mice

Abstract

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type-specific GPR109A expression in Gpr109a -/-mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE 2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid-induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin.

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

“…Hca2 À / À , Hca2 mRFP (Gpr109a mRFP ), CD11b-DTR, and Cox1 À / À mice have been reported previously 13,17,21,64 . The Hca2 À / À mice were backcrossed for more than eight generations on a C57BL/6 background; therefore, we used C57BL/6 mice as wild-type controls.…”

“…HCA 2 is activated by nicotinic acid, a drug that is used clinically to lower serum lipid concentrations 13 . In doses equal or lower than those used before in mice to exert clinically relevant effects 16,17 , nicotinic acid reduced the infarct size and the ischemic disruption of the blood-brain barrier (Fig. 2a,b).…”

“…However, the observations that nicotinic acid is able to penetrate into the brain 27 and that nicotinic acid treatment leads to elevated PGD 2 levels in the brain argue for an effect within the CNS. The protective effect of HCA 2 activation depended on COX1 and HPGDS, the key enzymes that synthesize PGD 2 in response to nicotinic acid treatment 17,41 . While we cannot exclude the possible involvement of COX2 or other arachidonic acid products, our data suggest a new concept by which PGD 2 release from monocytes/macrophages mediates the neuroprotective effect of HCA 2 .…”

“…To localize HCA 2 expression in the brain, we used the BAC-transgenic mouse line Hca2 mRFP (Gpr109a mRFP ), in which the Hca2 locus directs the expression of the monomeric red fluorescent protein (mRFP) 17 . Under normal conditions, mRFP was expressed exclusively by CD11b þ microglia, but not by astrocytes and neurons ( Fig.…”

Heating Up the Cutaneous Flushing Response

“…Past research has shown that, in particular, the vascular component of flushing is mediated by the hydroxycarboxylic acid receptor 2 (HCA 2 ), also known as G-protein-coupled receptor 109A (GPR109A), expressed in epidermal Langerhans cells and in keratinocytes and directly activated by nicotinic acid. 9 This is based on studies in HCA 2 -deficient mice and on the fact that many synthetic HCA 2 agonists also cause flushing. 8 Interestingly, the active metabolite of dimethyl fumarate, which was recently approved for the treatment of relapsing-remitting multiple sclerosis, 10 is also a HCA 2 agonist and causes flushing as well.…”