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

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

doi:10.1371/journal.pone.0222753

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

PLoS One. 2019 Sep 18;14(9):e0222753. doi: 10.1371/journal.pone.0222753. eCollection 2019.

Authors

Lei Yue¹, Min Yan², Michel L Tremblay³, Tong-Jun Lin^{4

5}, Hua Li¹, Ting Yang¹, Xia Song¹, Tianhong Xie¹, Zhongping Xie¹

Affiliations

¹ The Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan, China.
² Department of Microbiology and Immunology, Kunming Medical University, Kunming, Yunnan, China.
³ Rosalind and Morris Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
⁴ Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵ Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Cytokines / immunology
Cytokines / metabolism
Humans
Mice, Inbred C57BL
Mice, Knockout
Neutrophils / cytology
Neutrophils / immunology*
Neutrophils / metabolism
Nitric Oxide / immunology*
Nitric Oxide / metabolism
Nitric Oxide Synthase Type II / immunology
Nitric Oxide Synthase Type II / metabolism
Phagocytosis / immunology
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / immunology*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Pseudomonas Infections / immunology*
Pseudomonas Infections / metabolism
Pseudomonas Infections / microbiology
Pseudomonas aeruginosa / immunology*
Pseudomonas aeruginosa / physiology
STAT1 Transcription Factor / immunology
STAT1 Transcription Factor / metabolism
Signal Transduction / immunology
Toll-Like Receptor 4 / immunology
Toll-Like Receptor 4 / metabolism

Substances

Cytokines
STAT1 Transcription Factor
Stat1 protein, mouse
Toll-Like Receptor 4
Nitric Oxide
Nitric Oxide Synthase Type II
Nos2 protein, mouse
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Ptpn1 protein, mouse

Grants and funding

This work received grant support from National Natural Science Foundation of China (81800012) (http://www.nsfc.gov.cn), Yunnan Natural Science Foundation (2016FB037, 2017FB019) (http://kjt.yn.gov.cn/), PUMC Youth Fund (3332016114) (http://www.cams.ac.cn) and Fundamental Research Funds for the Central Universities (2016ZX350070) (http://www.cams.ac.cn) to LY. MY has received grant support from National Natural Science Foundation of China (31560271) (http://www.nsfc.gov.cn). TJL has received grant support from National Natural Science Foundation of China (81471564) (http://www.nsfc.gov.cn). ZX is supported by CAMS Innovation Fund for Medical Sciences (2016-I2M-1-019) (http://www.cams.ac.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.