PTP1B negatively regulates Pseudomonas aeruginosa killing by neutrophil through TLR4-STAT1-iNOS signaling

Abstract

Abstract Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals and chronic obstructive pulmonary diseases (COPD) patients. Mechanisms involved in immune responses to P. aeruginosa infection and bacterial clearance remain incompletely defined. Here we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa killing by neutrophil. PTP1B-deficient neutrophil display greatly enhanced bacterial killing capability and TLR4 transcription following P. aeruginosa infection. The negative regulation of PTP1B on the production of nitric oxide by neutrophil is blocked by TLR4 antagonist. Furthermore, the STAT1 activation in neutrophils following P. aeruginosa infection occurs in the downstream of TLR4, and PTP1B deficiency leads to enhanced TLR4 dependent STAT1 activation and iNOS expression by neutrophil. Interestingly, PTP1B deficiency mainly up-regulates the production of pro-inflammatory cytokines by neutrophil, including IL-6, IL-1β and TNFα, but only IL-6 is blocked by TLR4 antagonist. Further studies reveal that PTP1B and STAT1 are physically associated. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-STAT1 interaction. This novel PTP1B-STAT1-iNOS pathway may have broader implications in Toll-like receptor mediated innate immunity.