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PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils
Dongyan Song, … , Mikala Egeblad, Nicholas K. Tonks
Dongyan Song, … , Mikala Egeblad, Nicholas K. Tonks
Published July 22, 2022
Citation Information: JCI Insight. 2022;7(14):e158199. https://doi.org/10.1172/jci.insight.158199.
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Research Article Cell biology

PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils

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Abstract

Acute lung injury (ALI) can cause acute respiratory distress syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19. ARDS secondary to transfusion-related ALI (TRALI) has been recapitulated preclinically by anti–MHC-I antibody administration to LPS-primed mice. In this model, we demonstrate that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI and was associated with release of myeloperoxidase, suppression of neutrophil extracellular trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of PI3Kγ/AKT/mTOR, was essential for these effects, linking PTP1B inhibition to promoting an aged-neutrophil phenotype. Considering that dysregulated activation of neutrophils has been implicated in sepsis and causes collateral tissue damage, we demonstrate that PTP1B inhibitors improved survival and ameliorated lung injury in an LPS-induced sepsis model and improved survival in the cecal ligation and puncture–induced (CLP-induced) sepsis model. Our data highlight the potential for PTP1B inhibition to prevent ALI and ARDS from multiple etiologies.

Authors

Dongyan Song, Jose M. Adrover, Christy Felice, Lisa N. Christensen, Xue-Yan He, Joseph R. Merrill, John E. Wilkinson, Tobias Janowitz, Scott K. Lyons, Mikala Egeblad, Nicholas K. Tonks

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Figure 3

Treatment with MSI-1436 in vivo induced an aged-neutrophil phenotype.

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Treatment with MSI-1436 in vivo induced an aged-neutrophil phenotype.
(A...
(A) Reactome pathway analysis performed using g:Profiler for genes upregulated upon MSI-1436 treatment. (B) Representative confocal immunofluorescence microscopy images and quantification of neutrophils isolated from peripheral blood 2.5 hours after injection of saline or MSI-1436, and stained with anti-MPO (green) and DAPI (blue). Scale bars: 10 μm, n = 4 mice per group. (C) Neutrophils stained for MPO-containing granules from mice treated with saline or MSI-1436 for 2.5 hours. MPO signals were quantified as mean fluorescence intensity (MFI) (n = 4). (D) Surface expression of CD62L and CXCR2 on neutrophils from peripheral blood collected 2.5 hours after saline or MSI-1436 treatment, quantified as MFI (n = 5). Data are presented as mean ± SEM. Statistical analysis for B–D by 2-tailed Student’s t test. **P < 0.01, ***P < 0.001, ****P < 0.0001.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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