GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites,Nature

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GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites
Nature ( IF 50.5 ) Pub Date : 2019-01-23 , DOI: 10.1038/s41586-019-0884-1
Naoki Morita _{1,

2,

3} , Eiji Umemoto _{1,

2,

3} , Setsuko Fujita ₄ , Akio Hayashi ₄ , Junichi Kikuta _{2,

5} , Ikuo Kimura ₆ , Takeshi Haneda ₇ , Toshio Imai ₈ , Asuka Inoue ₉ , Hitomi Mimuro _{10,

11} , Yuichi Maeda _{1,

12} , Hisako Kayama _{1,

2,

3} , Ryu Okumura _{1,

2,

3} , Junken Aoki ₉ , Nobuhiko Okada ₇ , Toshiyuki Kida _{13,

14} , Masaru Ishii _{2,

5} , Ryusuke Nabeshima ₄ , Kiyoshi Takeda _{1,

2,

3,

14}

Affiliation

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.
WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.
Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
Ono Pharmaceutical Co. Ltd., Exploratory Research Laboratories, Mishima-Gun, Japan.
Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan.
Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan.
Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, Japan.
KAN Research Institute, Kobe, Japan.
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Infection Microbiology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Division of Bacteriology, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.

Small intestinal mononuclear cells that express CX3CR1 (CX3CR1+ cells) regulate immune responses1–5. CX3CR1+ cells take up luminal antigens by protruding their dendrites into the lumen1–4,6. However, it remains unclear how dendrite protrusion by CX3CR1+ cells is induced in the intestine. Here we show in mice that the bacterial metabolites pyruvic acid and lactic acid induce dendrite protrusion via GPR31 in CX3CR1+ cells. Mice that lack GPR31, which was highly and selectively expressed in intestinal CX3CR1+ cells, showed defective dendrite protrusions of CX3CR1+ cells in the small intestine. A methanol-soluble fraction of the small intestinal contents of specific-pathogen-free mice, but not germ-free mice, induced dendrite extension of intestinal CX3CR1+ cells in vitro. We purified a GPR31-activating fraction, and identified lactic acid. Both lactic acid and pyruvic acid induced dendrite extension of CX3CR1+ cells of wild-type mice, but not of Gpr31b−/− mice. Oral administration of lactate and pyruvate enhanced dendrite protrusion of CX3CR1+ cells in the small intestine of wild-type mice, but not in that of Gpr31b−/− mice. Furthermore, wild-type mice treated with lactate or pyruvate showed an enhanced immune response and high resistance to intestinal Salmonella infection. These findings demonstrate that lactate and pyruvate, which are produced in the intestinal lumen in a bacteria-dependent manner, contribute to enhanced immune responses by inducing GPR31-mediated dendrite protrusion of intestinal CX3CR1+ cells.In the mouse intestine, pyruvate and lactate produced from bacterial metabolites enhance immune responses through inducing dendrite protrusion, mediated by GPR31, of small intestinal mononuclear cells that express CX3CR1.

中文翻译：

细菌代谢物对肠道 CX3CR1+ 细胞的 GPR31 依赖性树突突出

表达 CX3CR1 的小肠单核细胞（CX3CR1+ 细胞）调节免疫反应 1-5。CX3CR1+ 细胞通过将树突伸入 lumen1-4,6 来吸收 luminal 抗原。然而，尚不清楚 CX3CR1+ 细胞如何在肠道中诱导树突突出。在这里，我们在小鼠身上展示了细菌代谢物丙酮酸和乳酸通过 CX3CR1+ 细胞中的 GPR31 诱导树突突出。缺乏 GPR31（在肠道 CX3CR1+ 细胞中高度选择性表达）的小鼠在小肠中表现出有缺陷的 CX3CR1+ 细胞树突突起。不含特定病原体的小鼠（而非无菌小鼠）的小肠内容物的甲醇可溶部分在体外诱导肠道 CX3CR1+ 细胞的树突延伸。我们纯化了 GPR31 激活部分，并鉴定了乳酸。乳酸和丙酮酸均诱导野生型小鼠 CX3CR1+ 细胞的树突延伸，但不会诱导 Gpr31b-/- 小鼠。乳酸和丙酮酸的口服给药增强了野生型小鼠小肠中 CX3CR1+ 细胞的树突突出，但在 Gpr31b-/- 小鼠的小肠中没有。此外，用乳酸或丙酮酸处理的野生型小鼠表现出增强的免疫反应和对肠道沙门氏菌感染的高抵抗力。这些发现表明，以细菌依赖性方式在肠腔中产生的乳酸和丙酮酸通过诱导 GPR31 介导的肠道 CX3CR1+ 细胞的树突突出来增强免疫反应。在小鼠肠道中，由细菌产生的丙酮酸和乳酸代谢物通过诱导由 GPR31 介导的树突突出来增强免疫反应，

更新日期：2019-01-23

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