ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

doi:10.3390/ijms19082371

Review

. 2018 Aug 12;19(8):2371.

doi: 10.3390/ijms19082371.

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

Akie Inami¹, Hiroshi Kiyono^{2

3

4

5

6}, Yosuke Kurashima^{7

8

9

10

11

12}

Affiliations

¹ Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. usajiro38@gmail.com.
² Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. kiyono@ims.u-tokyo.ac.jp.
³ International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. kiyono@ims.u-tokyo.ac.jp.
⁴ Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California, San Diego, CA 92093-0956, USA. kiyono@ims.u-tokyo.ac.jp.
⁵ Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. kiyono@ims.u-tokyo.ac.jp.
⁶ Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. kiyono@ims.u-tokyo.ac.jp.
⁷ Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. yosukek@chiba-u.jp.
⁸ International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. yosukek@chiba-u.jp.
⁹ Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California, San Diego, CA 92093-0956, USA. yosukek@chiba-u.jp.
¹⁰ Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. yosukek@chiba-u.jp.
¹¹ Department of Mucosal Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. yosukek@chiba-u.jp.
¹² Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. yosukek@chiba-u.jp.

PMID: 30103545
PMCID: PMC6121306
DOI: 10.3390/ijms19082371

Review

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

Akie Inami et al. Int J Mol Sci. 2018.

. 2018 Aug 12;19(8):2371.

doi: 10.3390/ijms19082371.

Authors

Akie Inami¹, Hiroshi Kiyono^{2

3

4

5

6}, Yosuke Kurashima^{7

8

9

10

11

12}

Affiliations

¹ Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. usajiro38@gmail.com.
² Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. kiyono@ims.u-tokyo.ac.jp.
³ International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. kiyono@ims.u-tokyo.ac.jp.
⁴ Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California, San Diego, CA 92093-0956, USA. kiyono@ims.u-tokyo.ac.jp.
⁵ Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. kiyono@ims.u-tokyo.ac.jp.
⁶ Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. kiyono@ims.u-tokyo.ac.jp.
⁷ Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. yosukek@chiba-u.jp.
⁸ International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. yosukek@chiba-u.jp.
⁹ Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California, San Diego, CA 92093-0956, USA. yosukek@chiba-u.jp.
¹⁰ Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. yosukek@chiba-u.jp.
¹¹ Department of Mucosal Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. yosukek@chiba-u.jp.
¹² Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. yosukek@chiba-u.jp.

PMID: 30103545
PMCID: PMC6121306
DOI: 10.3390/ijms19082371

Abstract

Extracellular nucleotides, such as adenosine triphosphate (ATP), are released from host cells including nerve termini, immune cells, injured or dead cells, and the commensal bacteria that reside in the gut lumen. Extracellular ATP interacts with the host through purinergic receptors, and promotes intercellular and bacteria-host communication to maintain the tissue homeostasis. However, the release of massive concentrations of ATP into extracellular compartments initiates acute and chronic inflammatory responses through the activation of immunocompetent cells (e.g., T cells, macrophages, and mast cells). In this review, we focus on the functions of ATP as a pathophysiologic mediator that is required for the induction and resolution of inflammation and inter-species communication.

Keywords: ATP; adenosine; commensal bacteria; inflammatory bowel disease (IBD); inter-species communication; purinergic pathway.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

**Figure 1**
ATP as a pathophysiologic mediator for bacteria-host communication. The pathways through which extracellular ATP (eATP) mediates communication between bacteria and host immune cells in the intestinal compartment are shown. Bacteria (e.g., *Escherichia coli*) produce ATP in a growth-phase-dependent manner and secrete it in outer membrane vesicles (OMVs). ATP derived from commensal bacteria leads to the differentiation of intestinal T helper 17 (Th17) cells through the stimulation of antigen-presenting cells. The reactive oxygen species (ROS) produced by adhesion of bacteria to epithelial cells promotes differentiation of Th17 cells. ATP activates mast cells and enhances inflammatory responses via P2X7 (e.g., chemical mediator release and inflammatory cell infiltration). In the small intestine, eATP released by commensal bacteria indirectly limits immunoglobulin A (IgA) responses to various bacteria by interacting with P2X7 on follicular helper T cells (Tfh cells), thus decreasing Tfh cell numbers. Purine metabolites, adenosine or inosine, inhibit inflammatory responses through interaction with adenosine receptors (e.g., A_2AR.). The dotted line arrow shows the eATP acts immune cells. The regular arrow shows induction of IgA producing B cells via cytokine production from Tfh cells.

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References

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1. Yegutkin G.G. Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim. Biophys. Acta. 2008;1783:673–694. doi: 10.1016/j.bbamcr.2008.01.024. - DOI - PubMed
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1. Atarashi K., Nishimura J., Shima T., Umesaki Y., Yamamoto M., Onoue M., Yagita H., Ishii N., Evans R., Honda K., et al. ATP drives lamina propria TH17 cell differentiation. Nature. 2008;455:808–812. doi: 10.1038/nature07240. - DOI - PubMed

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[1] Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 2007;87:659–797. doi: 10.1152/physrev.00043.2006. - DOI - PubMed

[2] Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 2007;87:659–797. doi: 10.1152/physrev.00043.2006. - DOI - PubMed

[3] Yegutkin G.G. Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim. Biophys. Acta. 2008;1783:673–694. doi: 10.1016/j.bbamcr.2008.01.024. - DOI - PubMed

[4] Yegutkin G.G. Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim. Biophys. Acta. 2008;1783:673–694. doi: 10.1016/j.bbamcr.2008.01.024. - DOI - PubMed

[5] Gillespie J.H. The biological significance of the linkages in adenosine triphosphoric acid. J. Physiol. 1934;80:345–359. doi: 10.1113/jphysiol.1934.sp003095. - DOI - PMC - PubMed

[6] Gillespie J.H. The biological significance of the linkages in adenosine triphosphoric acid. J. Physiol. 1934;80:345–359. doi: 10.1113/jphysiol.1934.sp003095. - DOI - PMC - PubMed

[7] Ralevic V., Burnstock G. Receptors for purines and pyrimidines. Pharmacol. Rev. 1998;50:413–492. - PubMed

[8] Ralevic V., Burnstock G. Receptors for purines and pyrimidines. Pharmacol. Rev. 1998;50:413–492. - PubMed

[9] Atarashi K., Nishimura J., Shima T., Umesaki Y., Yamamoto M., Onoue M., Yagita H., Ishii N., Evans R., Honda K., et al. ATP drives lamina propria TH17 cell differentiation. Nature. 2008;455:808–812. doi: 10.1038/nature07240. - DOI - PubMed

[10] Atarashi K., Nishimura J., Shima T., Umesaki Y., Yamamoto M., Onoue M., Yagita H., Ishii N., Evans R., Honda K., et al. ATP drives lamina propria TH17 cell differentiation. Nature. 2008;455:808–812. doi: 10.1038/nature07240. - DOI - PubMed

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ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

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ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

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