Protein Tyrosine Phosphatase-1B Negatively Impacts Host Defense against Pseudomonas aeruginosa Infection

Abstract

Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals. Mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa infection. PTP1B-deficient mice display greatly enhanced bacterial clearance and reduced disease scores, which are accompanied by increased neutrophil infiltration and cytokine production. Interestingly, PTP1B deficiency mainly up-regulates the production of interferon-stimulated response elements-regulated cytokines and chemokines, including chemokine ligand 5 (regulated on activation normal T cell expressed and secreted), CXCL10 (interferon γ-inducible protein 10), and interferon-β production. Further studies reveal that PTP1B deficiency leads to increased interferon regulatory factor 7 (IRF7) expression and activation. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-IRF7 interaction. This novel PTP1B-IRF7-interferon-stimulated response elements pathway may have broader implications in Toll-like receptor-mediated innate immunity.

CXCL4 contributes to host defense against acute Pseudomonas aeruginosa lung infection

“…aeruginosa lung infection via unique mechanisms. Previously, we demonstrated essential roles of macrophages[ 29 ], mast cells[ 43 ] and dendritic cells[ 44 ] in an acute P . aeruginosa infection model.…”

Role of negative regulation of immune signaling pathways in neutrophil function

“…Vav-1 and TIPE-2 also inhibits Rac activation and therefore, suppress ROS production [59, 60]. Phosphatases such as PTP1B and PTEN negatively regulates phagocytosis [36]. PTEN also regulates ROS production by regulating the availability of PtdIns(3,4,5)P3 [41].…”

“…59,60 Phosphatases such as PTP1B and PTEN negatively regulates phagocytosis. 36 PTEN also regulates ROS production by regulating the availability of PtdIns(3,4,5)P3. 41 Because it is well described that NET formation depends of ROS production, it is possible that negative regulators of ROS production are also potentially inhibiting NETosis.…”

“…Activated PTP1B can in turn act as a common negative regulator of NFκB, Akt and MAPK activities. In keeping with its role as a negative regulator of immune cell function Ptp1b KO mice exhibited higher accumulation of PMN (as measured by myeloperoxidase (MPO) levels and severity of edema) in the ear in response to LPS or Zymosan [35] and in the lungs in response to P. aeruginosa [36]. Similarly, in a respiratory syncytial virus (RSV) model of lung inflammation, loss of PTP1B expression resulted in changes in cytokine signaling, elevated PMN accumulation and increased damage and disruption of the epithelial cell barrier [37].…”

“…Another phosphatase, the ubiquitous tyrosine phosphatase PTP1B has been shown to negatively regulate PMN function. In a P. aeruginosa infection model, Ptp1b −/− mice displayed enhanced bacterial clearance accompanied by increased PMN infiltration in the lungs, suggesting increased phagocytosis in the absence of PTP1B [36]. However, further analysis dissecting the individual roles of PMN and macrophages in bacterial clearance is necessary in order to conclude PTP1B negatively regulates PMN phagocytosis.…”