A new discovery of ectoenzyme that hydrolyzes ATP E-NTPD8 reduces the severity of colitis

Oct, 2021 - by CMI


A team lead by Osaka University researchers discovered a biological mechanism that inhibits colitis aggravation by regulating intestine levels of a microbial metabolite called adenosine triphosphate.

Luminal ATP, a type of ATP secreted by bacteria in the intestine, impacts the immune system of the host, the amount of luminal ATP is closely controlled to avoid intestinal inflammation. The precise mechanism for regulating luminal ATP levels in the colon, however, is unknown. The contribution of an ATP-hydrolyzing enzyme known as ectonucleoside triphosphate di phosphohydrolase 8 (E-NTPD8) in the colon was explored in this research. To prevent unnecessary immune responses, enzymes from the E-NTPD family can decompose ATP molecules into adenosine diphosphate or adenosine monophosphate, a process known as ATP hydrolysis.

The researchers discovered that E-NTPD8 can hydrolyze ATP given to the cell culture medium in cell culture tests. They created a model system using mice lacking the gene encoding the E-NTPD8 protein to examine the particular impact of this activity in vivo. Moreover, the team discovered that the E-NTPD8 knockout mice had more serious symptoms after chemically inducing colitis. Th17 cells and neutrophils, two types of immune cells, were also observed at higher numbers in the colons of these animals. The use of a specific antibody to deplete neutrophils significantly improved severe colitis symptoms in these mice, but depletion of many other immune cell types did not.

The researchers discovered that luminal ATP promotes glycolysis in neutrophils via P2X4R, which increases their lifespan. As a result of the accumulation of neutrophils in the colon, there is an increase in inflammation. Millions of people around the world suffer from inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. This group's significant findings point in a potential direction for the development of novel therapy techniques for various illnesses.