Abstract
Sepsis is defined as an uncontrolled host response to infection, and no specific therapy or drugs have been used in clinical trials currently. Discovering new therapeutic targets for sepsis treatment has always been a central problem in the field of sepsis research. Neutrophils stand at the first line in controlling infection and have been identified to be dysregulated with impaired migration and antimicrobial function during sepsis. Based on our previous results on demonstrating wild-type p53-induced phosphatase 1 in controlling neutrophil development, we explored the possible relationship among Wip1, neutrophils, and sepsis in the present study. Wip1-deficient mice exhibited improved outcomes in cecal ligation and puncture (CLP)-induced sepsis model with enhanced bacterial clearance and less multi-organ damage. The protection seen in Wip1 KO mice was mainly due to an increased accumulation of neutrophils in the primary infectious locus mediated by the decreased internalization of CXCR2, as well as by an increased antimicrobial function. Additionally, we also identified a negative correlation between CXCR2 and Wip1 in human neutrophils during sepsis. Pharmacological inhibition of Wip1 with its inhibitor can also prevent the internalization of CXCR2 on human neutrophils treated with lipopolysaccharides in vitro and significantly improve the outcome in CLP-induced sepsis model. Taken together, our results demonstrate that Wip1 can negatively regulate neutrophil migration and antimicrobial immunity during sepsis and inhibition of Wip1 can be a potential therapeutic target for sepsis treatment.
Highlights
Sepsis is defined as a dysregulated host response to infection [1, 2] and is still a major cause of death in hospitalized patients
WT mice all died by 72 h after cecal ligation and puncture (CLP) surgery as described previously [13], while Wip1 Knock-out (Wip1 KO) were highly resistant to CLP-induced lethality with more than half of the mice were still alive at day 7 (Figure 1A)
We examined whether resistance to CLP-induced sepsis in Wip1 KO mice was related to an enhanced bacterial clearance
Summary
Sepsis is defined as a dysregulated host response to infection [1, 2] and is still a major cause of death in hospitalized patients. The difficulty in finding novel therapeutic strategies for sepsis is the complicated pathophysiology process, which can be defined as an interplay between host pro-inflammatory and anti-inflammatory responses [3]. Wip Deficiency Improves Sepsis Outcome infection and/or the acquisition of secondary hospital-acquired infection due to the altered immune function [4]. Both innate and adaptive immune responses have been altered after such “recovery” from acute events with a predominant immunosuppression status [5]. Efforts focused on reversing the immune cell dysfunction may be a promising perspective in the area of sepsis research
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