The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells

  • Proc Natl Acad Sci U S A. 2021 Sep 28;118(39):e2100594118. doi: 10.1073/pnas.2100594118.
Haruka Tani  1 ,  Bo Li  1 ,  Takashi Kusu  1 ,  Ryu Okumura  1  2 ,  Junichi Nishimura  1 ,  Daisuke Okuzaki  2  3 ,  Daisuke Motooka  3  4 ,  Shoya Arakawa  5 ,  Asuka Mori  5 ,  Terukazu Yoshihara  6 ,  Takayuki Ogino  6 ,  Shih-Han Tsai  1 ,  Yoki Furuta  1 ,  Masato Muneta  1 ,  Shota Nakamura  3  4 ,  Eiichiro Fukusaki  5 ,  Kimiko Yamamoto  7 ,  Hideo Yagita  8 ,  Hisako Kayama  9  2  10 ,  Kiyoshi Takeda  9  2  3
Affiliations
  • 1. Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 2. The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
  • 3. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan.
  • 4. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 5. Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.
  • 6. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  • 7. Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
  • 8. Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
  • 9. Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; [email protected] [email protected].
  • 10. Institute for Advanced Co-Creation Studies, Osaka University, Osaka 565-0871, Japan.
PMID: 34548395 DOI: 10.1073/pnas.2100594118
Abstract

Extracellular Adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8-/- mice develop more severe dextran sodium sulfate-induced Colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8-/- mice promotes Glycolysis in neutrophils through P2x4 receptor-dependent CA2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward Glycolysis via the P2X4 Receptor in myeloid cells.

Keywords
E-NTPD8; P2X4R; adenosine triphosphate; colitis; immunometabolism.