Neutrophils as sources of dinucleotide polyphosphates and metabolism by epithelial ENPP1 to influence barrier function via adenosine signaling

被引:17
作者
Curtis, Valerie F. [1 ,2 ]
Cartwright, Ian M. [1 ,2 ]
Lee, J. Scott [1 ,2 ]
Wang, Ruth X. [1 ,2 ]
Kao, Daniel J. [1 ,2 ]
Lanis, Jordi M. [1 ,2 ]
Burney, Krista M. [1 ,2 ]
Welch, Nichole [1 ,2 ]
Hall, Caroline H. T. [1 ,2 ]
Goldberg, Matthew S. [1 ,2 ]
Campbell, Eric L. [1 ,2 ,3 ]
Colgan, Sean P. [1 ,2 ,4 ]
机构
[1] Univ Colorado, Mucosal Inflammat Program, Anschutz Med Campus, Aurora, CO 80045 USA
[2] Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO 80045 USA
[3] Queens Univ Belfast, Ctr Expt Med, Belfast BT7 1NN, Antrim, North Ireland
[4] Rocky Mt Vet Affairs Hosp, Denver, CO 80220 USA
基金
美国国家卫生研究院;
关键词
HYPOXIA; TIGHT; CD73; PERMEABILITY; MECHANISMS; CELLS; MONOPHOSPHATE; INFLAMMATION; HOMEOSTASIS; EXPRESSION;
D O I
10.1091/mbc.E18-06-0377
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Extracellular adenosine signaling is established as a protective component in mucosal inflammatory responses. The sources of extracellular adenosine include enzymatic processing from nucleotides, such as ATP and AMP, that can be liberated from a variety of cell types, including infiltrating leukocytes. Here we demonstrate that activated human neutrophils are a source of diadenosine triphosphate (Ap3A), providing an additional source of nucleotides during inflammation. Profiling murine enteroids and intestinal epithelial cell lines revealed that intestinal epithelia prominently express apical and lateral ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a member of the ENPP family of enzymes that metabolize diadenosine phosphates, especially Ap3A. Extensions of these studies demonstrated that intestinal epithelia metabolize Ap3A to ADP and AMP, which are further metabolized to adenosine and made available to activate surface adenosine receptors. Using loss and gain of ENPP1 approaches, we revealed that ENPP1 coordinates epithelial barrier formation and promotes epithelial wound healing responses. These studies demonstrate the cooperative metabolism between Ap3A and ENPP1 function to provide a significant source of adenosine, subserving its role in inflammatory resolution.
引用
收藏
页码:2687 / 2699
页数:13
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