PTP1B negatively regulates nitric oxide-mediated Pseudomonas aeruginosa killing by neutrophils.

Lei Yue,Hua Li,Zhongping Xie,Ting Yang,Xia Song,Tong-Jun Lin,Michel L Tremblay,Min Yan,Tianhong Xie,Samithamby Jeyaseelan

doi:10.1371/journal.pone.0222753

Abstract

Neutrophils play a critical role in host defense against Pseudomonas aeruginosa infection. Mechanisms underlying the negative regulation of neutrophil function in bacterial clearance remain incompletely defined. Here, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a negative regulator of P. aeruginosa clearance by neutrophils. PTP1B-deficient neutrophils display greatly enhanced bacterial phagocytosis and killing, which are accompanied by increased Toll-like receptor 4 (TLR4) signaling activation and nitric oxide (NO) production following P. aeruginosa infection. Interestingly, PTP1B deficiency mainly upregulates the production of IL-6 and IFN-β, leads to enhanced TLR4-dependent STAT1 activation and iNOS expression by neutrophils following P. aeruginosa infection. Further studies reveal that PTP1B and STAT1 are physically associated. These findings demonstrate a negative regulatory mechanism in neutrophil underlying the elimination of P. aeruginosa infection though a PTP1B-STAT1 interaction.

Highlights

Pseudomonas aeruginosa is a prevalent opportunistic pathogen that is the common cause of exacerbations of chronic obstructive pulmonary disease (COPD)[1] and community acquired pneumonia (CAP)[2]
To examine whether protein tyrosine phosphatase-1B (PTP1B) affects the phagocytosis of P. aeruginosa, bone marrow-derived neutrophils from wild-type or PTP1B-deficient mice were infected with P. aeruginosa strain 8821
To investigate the effects underlying the negative regulation of PTP1B in phagocytosis, qPCR array assays were performed with the P. aeruginosa-infected wild-type or PTP1B-deficient neutrophils

Summary

Introduction

Pseudomonas aeruginosa is a prevalent opportunistic pathogen that is the common cause of exacerbations of chronic obstructive pulmonary disease (COPD)[1] and community acquired pneumonia (CAP)[2]. It is the predominant pathogen-based cause of morbidity and mortality in cystic fibrosis (CF) patients[3, 4]. The innate immune response plays a critical role in host defense against P. aeruginosa infection[5]. This immune process requires the effective production of cytokines and chemokines to recruit neutrophils to inflammatory sites, which culminates in the phagocytosis and killing of the bacterium[6, 7]. A key factor for controlling P. aeruginosa is the maintenance of a balanced immune response, which effectively eliminates

Methods

Results

Conclusion