TY - JOUR
T1 - GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites
AU - Morita, Naoki
AU - Umemoto, Eiji
AU - Fujita, Setsuko
AU - Hayashi, Akio
AU - Kikuta, Junichi
AU - Kimura, Ikuo
AU - Haneda, Takeshi
AU - Imai, Toshio
AU - Inoue, Asuka
AU - Mimuro, Hitomi
AU - Maeda, Yuichi
AU - Kayama, Hisako
AU - Okumura, Ryu
AU - Aoki, Junken
AU - Okada, Nobuhiko
AU - Kida, Toshiyuki
AU - Ishii, Masaru
AU - Nabeshima, Ryusuke
AU - Takeda, Kiyoshi
N1 - Funding Information:
Acknowledgements We thank F. Sugiyama (University of Tsukuba) for his kind gift of B6J-S1UTR embryonic stem cell line; T. Kamisako, M. Kumai, Y. Izumi, H. Ishizaki and Y. Ono (KAN Research Institute) for their kind supply of Cx3cl1−/− mice; T. Kondo and Y. Magota for technical assistance; and C. Hidaka for secretarial assistance. This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15H02511 and 16K08838), and Japan Agency for Medical Research and Development (J170701434).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/2/7
Y1 - 2019/2/7
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-0884-1
DO - 10.1038/s41586-019-0884-1
M3 - Article
C2 - 30675063
AN - SCOPUS:85061132591
VL - 566
SP - 110
EP - 114
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7742
ER -