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

Naoki Morita; Eiji Umemoto; Setsuko Fujita; Akio Hayashi; Junichi Kikuta; Ikuo Kimura; Takeshi Haneda; Toshio Imai; Asuka Inoue; Hitomi Mimuro; Yuichi Maeda; Hisako Kayama; Ryu Okumura; Junken Aoki; Nobuhiko Okada; Toshiyuki Kida; Masaru Ishii; Ryusuke Nabeshima; Kiyoshi Takeda

doi:10.1038/s41586-019-0884-1

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

Nature. 2019 Feb;566(7742):110-114. doi: 10.1038/s41586-019-0884-1. Epub 2019 Jan 23.

Authors

Naoki Morita^#^{1

2

3}, Eiji Umemoto^#^{1

2

3}, Setsuko Fujita⁴, Akio Hayashi⁴, Junichi Kikuta^{2

5}, Ikuo Kimura⁶, Takeshi Haneda⁷, Toshio Imai⁸, Asuka Inoue⁹, Hitomi Mimuro^{10

11}, Yuichi Maeda^{1

12}, Hisako Kayama^{1

2

3}, Ryu Okumura^{1

2

3}, Junken Aoki⁹, Nobuhiko Okada⁷, Toshiyuki Kida^{13

14}, Masaru Ishii^{2

5}, Ryusuke Nabeshima⁴, Kiyoshi Takeda^{15

16

17

18}

Affiliations

¹ Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.
² WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.
³ Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
⁴ Ono Pharmaceutical Co. Ltd., Exploratory Research Laboratories, Mishima-Gun, Japan.
⁵ Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Japan.
⁶ Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan.
⁷ Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, Japan.
⁸ KAN Research Institute, Kobe, Japan.
⁹ Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
¹⁰ Department of Infection Microbiology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
¹¹ Division of Bacteriology, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹² Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.
¹³ Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Japan.
¹⁴ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
¹⁵ Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan. ktakeda@ongene.med.osaka-u.ac.jp.
¹⁶ WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. ktakeda@ongene.med.osaka-u.ac.jp.
¹⁷ Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan. ktakeda@ongene.med.osaka-u.ac.jp.
¹⁸ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan. ktakeda@ongene.med.osaka-u.ac.jp.

^# Contributed equally.

PMID: 30675063
DOI: 10.1038/s41586-019-0884-1

Abstract

Small intestinal mononuclear cells that express CX3CR1 (CX3CR1⁺ cells) regulate immune responses^1-5. CX3CR1⁺ cells take up luminal antigens by protruding their dendrites into the lumen^1-4,6. 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacteria / immunology
Bacteria / metabolism*
CX3C Chemokine Receptor 1 / deficiency
CX3C Chemokine Receptor 1 / genetics
CX3C Chemokine Receptor 1 / metabolism*
Cell Surface Extensions / drug effects
Cell Surface Extensions / immunology
Cell Surface Extensions / metabolism*
Female
HEK293 Cells
Humans
Intestine, Small / cytology*
Intestine, Small / drug effects
Intestine, Small / immunology
Intestine, Small / microbiology*
Lactic Acid / metabolism*
Lactic Acid / pharmacology
Lactobacillus helveticus / metabolism
Male
Methanol
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Pyruvic Acid / metabolism*
Pyruvic Acid / pharmacology
Receptors, G-Protein-Coupled / deficiency
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Salmonella / immunology
Salmonella / metabolism

Substances

CX3C Chemokine Receptor 1
Cx3cr1 protein, mouse
GPR31 protein, human
Gpr31 protein, mouse
Receptors, G-Protein-Coupled
Lactic Acid
Pyruvic Acid
Methanol