The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages
The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages
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DOI：
10.1038/ncomms4944
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发表时间：
2014-05-01
影响因子：
16.6
通讯作者：
Schwaninger, Markus
中科院分区：
文献类型：
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作者：
Rahman, Mahbubur;Muhammad, Sajjad;Schwaninger, Markus
酮体β-羟基丁酸酯（BHB）是一种内源性因子，可预防中风和神经退行性疾病，但其作用方式尚不清楚。在这里，我们在中风模型中表明，羟基羧酸受体2（HCA（2），GPR 109 A）是BHB和生酮饮食的神经保护作用所必需的，因为这种作用在Hca 2（-/-）小鼠中丧失。我们进一步证实了烟酸，一种临床上使用的HCA（2）激动剂，通过HCA（2）介导的机制减少梗死面积，并且浸润缺血脑的非炎性Ly-6C（Lo）单核细胞和/或巨噬细胞也表达HCA（2）。使用细胞消融和嵌合小鼠，我们证明单核细胞和/或巨噬细胞上的HCA（2）是烟酸保护作用所必需的。HCA（2）的激活诱导单核细胞和/或巨噬细胞的神经保护表型，其依赖于COX 1和造血PGD 2合酶产生PGD（2）。我们的数据表明，通过饮食或药物手段激活HCA（2）指示Ly-6C（Lo）单核细胞和/或巨噬细胞向大脑传递神经保护信号。
The ketone body beta-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(-/-) 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 PGD2 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.