E-NPP3 controls plasmacytoid dendritic cell numbers in the small intestine

PLoS One. 2017 Feb 22;12(2):e0172509. doi: 10.1371/journal.pone.0172509. eCollection 2017.

Abstract

Extracellular adenosine 5'-triphosphate (ATP) performs multiple functions including activation and induction of apoptosis of many cell types. The ATP-hydrolyzing ectoenzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3) regulates ATP-dependent chronic allergic responses by mast cells and basophils. However, E-NPP3 is also highly expressed on epithelial cells of the small intestine. In this study, we showed that E-NPP3 controls plasmacytoid dendritic cell (pDC) numbers in the intestine through regulation of intestinal extracellular ATP. In Enpp3-/- mice, ATP concentrations were increased in the intestinal lumen. pDC numbers were remarkably decreased in the small intestinal lamina propria and Peyer's patches. Intestinal pDCs of Enpp3-/- mice showed enhanced cell death as characterized by increases in annexin V binding and expression of cleaved caspase-3. pDCs were highly sensitive to ATP-induced cell death compared with conventional DCs. ATP-induced cell death was abrogated in P2rx7-/- pDCs. Accordingly, the number of intestinal pDCs was restored in Enpp3-/- P2rx7-/- mice. These findings demonstrate that E-NPP3 regulates ATP concentration and thereby prevents the decrease of pDCs in the small intestine.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Caspase 3 / metabolism
  • Cell Death / physiology
  • Dendritic Cells / metabolism*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism
  • Intestine, Small / cytology*
  • Intestine, Small / metabolism
  • Mice
  • Mice, Knockout
  • Peyer's Patches / metabolism
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrophosphatases / genetics
  • Pyrophosphatases / metabolism*

Substances

  • E-NPP3 protein, mouse
  • Adenosine Triphosphate
  • Phosphoric Diester Hydrolases
  • Caspase 3
  • Pyrophosphatases

Grant support

Support was provided by: the Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Science and Technology Agency (Recipient: Kiyoshi Takeda, T15K15152, A15H02511); Japan Agency for Medical Research and Development (Recipient: Kiyoshi Takeda, 15gm011002h0006); and Mochida Memorial Foundation for Medical and Pharmaceutical (Recipient: Shih-Han Tsai).