Phosphatase Wip1 as a new therapeutic target for intestinal ischemia-reperfusion injury

Abstract

Intestinal ischemia/reperfusion (I/R) injury is a pathophysiology involving local tissue injury and organ dysfunction. Accumulating evidence has confirmed that the infiltration of neutrophils is of central importance in mediating intestinal I/R injury. On the other hand, adequate neutrophils in the intestine could also benefit the antibacterial translocation and tissue repair. Consequently, regulation of neutrophil immunity after intestinal I/R might be a promising therapy for controlling intestinal injury. Wip1 is a serine/threonine protein phosphatase that acts as the master regulator of tumorigenesis. However, emerging evidence highlights the importance of Wip1 in regulating neutrophil development, maturation, migration and neutrophil pro-inflammatory cytokine productions. Our recent studies showed that Wip1 negatively regulates neutrophil inflammatory responses and plays a protective role in intestinal I/R injury. In light of this discovery, we believe that Wip1 might be a new therapeutic target for treating intestinal I/R injury.

Keywords::

• intestinal ischemia/reperfusion injury
• neutrophils
• Wip1

Acknowledgements

We thank Mr. Steven Shao for his careful reviewing our manuscript.

Financial & competing interests disclosure

This work was supported by grants from the National Basic Research Program of China (2010CB945301, 2011CB710903, Y Zhao), the National Natural Science Foundation for General and Key Programs (C81130055, C81072396, Y Zhao; 81372364, 81000189, W Guan), and Knowledge Innovation Program of Chinese Academy of Sciences (XDA04020202-19, Y Zhao), the CAS/SAFEA International Partnership Program for Creative Research Teams (Y Zhao), the China Postdoctoral Science Foundation (2014M552695, X Shen). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Intestinal ischemia/reperfusion (I/R) injury is a major challenge during intestine transplantation, superior mesenteric artery embolus and general surgery. Currently, there are no ideal therapies for treating intestinal I/R injury.

• Intestinal I/R injury is often characterized as a neutrophil-driven pathology, and better control of neutrophil infiltration in local and remote tissues, as well as their pro-inflammatory cytokine production, is crucial to treating intestinal I/R injury.

• Phosphatase Wip1 acts as a master regulator for neutrophil immunity, which influences the development and maturation of neutrophils and their antimicrobial and inflammatory activities.

• The Wip1 expression level was negatively correlated with inflammatory cytokine productions of neutrophils in sepsis patients. Wip1-deficient mice were also hypersensitive to Lipopolysaccharide-induced acute lung injury.

• Neutrophil immunity is tightly controlled by Wip1, and targeting Wip1 may be a promising approach for treating I/R injury.