Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.
Department of Translational Research and Cellular Therapeutics, School of Medicine, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.
J Neuroinflammation. 2021 Dec 27;18(1):304. doi: 10.1186/s12974-021-02361-2.
Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D (PGD) production and PGD-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans.
To reveal the relationship between PGD-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function with gene and protein expression, histological, and behavioral analysis in GPR120 knockout (KO) mice.
In the current study, we discovered notable neuroinflammation (increased PGD production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic-prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD production attenuated this neuroinflammation. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 contents. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice.
Our results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD-microglia-provoked neuroinflammation in the hippocampus.
神经炎症是神经退行性疾病的关键病理组成部分，其特征为小胶质细胞激活和促炎介质的分泌。我们之前的研究报告指出，前列腺素 D（PGD）的大量产生和 PGD 诱导的小胶质细胞激活可能引发神经炎症。我们还报告称，一种在肠道中表达的脂质传感器 GPR120（游离脂肪酸受体 4）可以被多不饱和脂肪酸（PUFA）激活，从而介导胰高血糖素样肽-1（GLP-1）的分泌。GPR120 功能障碍可导致人和小鼠肥胖。
为了揭示 PGD-小胶质细胞引发的神经炎症与肠道 PUFA/GPR120 信号之间的关系，我们通过基因和蛋白表达、组织学和行为分析，在 GPR120 敲除（KO）小鼠中研究了神经炎症和神经元功能。
在目前的研究中，我们发现 GPR120 KO 小鼠存在明显的神经炎症（PGD 产生增加和小胶质细胞激活）和神经退行性变（神经发生减少、海马体积缩小和认知功能下降）。我们还发现，造血前列腺素 D 合酶（H-PGDS）在小胶质细胞中表达，PGD 可激活小胶质细胞，GPR120 KO 海马中的 H-PGDS 表达上调，抑制 PGD 产生可减轻这种神经炎症。GPR120 KO 小鼠的肠道、血浆和脑内 GLP-1 含量减少。外周给予 GLP-1 类似物利拉鲁肽可减轻 GPR120 KO 小鼠的 PGD-小胶质细胞引发的神经炎症和进一步的神经退行性变。
我们的研究结果表明，GPR120 KO 小鼠的神经表型可能是由于肠道 GPR120 功能障碍引起的。这些观察结果提示，肠道 GPR120 刺激的肠道 GLP-1 分泌可能远程抑制海马中 PGD-小胶质细胞引发的神经炎症。
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