E-NTPD8, an external enzyme that hydrolyzes ATP, reduces colitis

Colon epithelial cells E-NTPD8 maintain intestinal homeostasis through hydrolysis of luminal ATP produced by symbiotic bacteria (left). Increased levels of luminal ATP caused by the lack of E-NTPD8 regulate neutrophil physiology, including prolonged survival by promoting P2X4-mediated glycolysis. This can exacerbate the symptoms of colitis (right).Credit: Haruka Tani and others

The intestinal microbial ecosystem contains a wide variety of bacteria. These bacteria can produce bioactive metabolites that directly affect the host’s immune system. The imbalance of microbial metabolites is associated with the pathogenesis of chronic diseases, including ulcerative colitis.In a recent article published in PNASA team led by researchers at Osaka University suppressed the exacerbation of colitis through the regulation of intestinal levels of adenosine triphosphate (ATP), a microbial metabolite that affects specific immune cells and promotes the inflammatory response. I discovered the molecular mechanism of inflammation.

ATP secreted by gut bacteria, known as luminal ATP, affects the host’s immune system, so the amount of luminal ATP is tightly controlled to prevent intestinal inflammation. However, the specific mechanism for regulating luminal ATP levels in the colon is not fully understood. In this study, the research group investigated the role of an ATP hydrolase called ectonucleoside triphosphate diphosphohydrolase 8 (E-NTPD8) in the colon.

Enzymes belonging to the E-NTPD family can break down ATP molecules into adenosine diphosphate or adenosine monophosphate. This is called ATP hydrolysis and blocks an inappropriate immune response. Researchers conducted cell culture experiments and discovered that E-NTPD8 can hydrolyze ATP added to cell culture media.To investigate the specific impact of this activity In vivo, They generated a model system in mice lacking the gene encoding the E-NTPD8 protein.

“In knockout mice, E-NTPD8 expression was completely abolished in colonic epithelial cells, but in wild-type mice, this protein was highly expressed in these cells,” said Kiyoshi Takeda, the lead author. .. “The colon of knockout mice also had much higher levels of luminal ATP.”

In addition, the team observed more after chemically inducing colitis. Severe symptoms With E-NTPD8 Knockout mouse..These animals also had a high number of Th17 cell And colon neutrophils Immune cells.. Treatment of these mice with specific antibodies to deplete neutrophils significantly improved the symptoms of severe colitis, but not the depletion of various other immune cell types.

“Additional mechanical experiments have shown that the molecular interaction between ATP and a receptor called P2X4R is important here,” explains senior author Hisako Kayama. “In mice lacking both E-NTPD8 and P2X4R, the disease improved significantly and the number of neutrophils decreased compared to normal. mouse.. “

The team determined that luminal ATP promoted a process called glycolysis via P2X4R of neutrophils, which could prolong neutrophil survival. This ultimately leads to an increase in inflammation caused by the accumulation of neutrophils in the colon.

“Our data suggest that luminal ATP-P2X4R signaling and regulation of E-NTPD8 expression levels can be used for therapeutic intervention in humans. Ulcerative colitis“Kayama explains.

Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease have a negative impact on the lives of millions of people around the world. The influential data presented by this group provide promising directions for the development of new treatments for these disorders.

“This study identifies a mechanism for reducing the number of neutrophils. colon Prevents severe colitis. We hope that our research results will lead to the elucidation of the etiology of ulcerative colitis and the development of new treatments. I would like to express my sincere gratitude to my colleagues and the patients who provided the samples. ”

Potential new therapeutic approaches for chronic inflammatory bowel disease

For more information:
E-NTPD8, an external enzyme that hydrolyzes ATP, reduces colitis through the regulation of P2X4 receptor-dependent metabolism in bone marrow cells. PNAS, DOI: 10.1073 / pnas.2100594118

Provided by
Osaka University

Quote: ATP hydrolyzable external enzyme E-NTPD8 was obtained from on September 20, 2021. Reduces colitis (September 20, 2021)

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E-NTPD8, an external enzyme that hydrolyzes ATP, reduces colitis

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