Disarming the immune system's lethal lung response CSHL JCI_Insight
). In this current study, we demonstrate that a single dose of either of 2 distinct allosteric inhibitors of PTP1B induced a phenotype that exhibited features of neutrophil aging. This coincided with attenuation of lung injury and decreased mortality in a murine, neutrophil-dependent TRALI model of ARDS and the LPS-induced endotoxemia model of sepsis. Furthermore, PTP1B inhibitor MSI-1436 also improved survival in the CLP-induced model of sepsis.
Both MSI-1436 and DPM-1003 are allosteric inhibitors that primarily target the noncatalytic, disordered segment in the C-terminus of PTP1B. This segment is a unique portion of the PTP1B protein that is unrelated to TC-PTP . Consequently, we expect that such inhibitors have the potential to be highly specific for PTP1B over other members of the PTP family.
The process of neutrophil aging features a cell-intrinsic signaling module, in which chemokine receptors CXCR2 and CXCR4 functionally oppose one another. CXCR2 promotes mobilization of neutrophils into the blood stream, whereas CXCR4 retains neutrophils in the BM, with CXCR4 playing a dominant role over CXCR2 .