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

Song, Dongyan, Adrover, Jose M, Felice, Christy, Christensen, Lisa N, He, Xue-Yan, Merrill, Joseph R, Wilkinson, John E, Janowitz, Tobias, Lyons, Scott K, Egeblad, Mikala, Tonks, Nicholas K (July 2022) PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils. JCI Insight, 7 (14). e158199. ISSN 2379-3708

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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.

Item Type:	Paper
Subjects:	diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle > Neutrophil extracellular traps diseases & disorders > viral diseases organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > viral diseases > coronavirus diseases & disorders > viral diseases > coronavirus > covid 19 organs, tissues, organelles, cell types and functions > organs types and functions > lung organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent
CSHL Authors:	Felice, Christy He, Xueyan Merrill, Joseph Janowitz, Tobias Lyons, Scott Egeblad, Mikala Tonks, Nicholas K. Christensen, Lisa N. Song, Dongyan Adrover, Jose M.
Communities:	CSHL labs > Egeblad lab CSHL labs > Janowitz lab CSHL labs > Lyons lab CSHL labs > Tonks lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Histology Service CSHL Cancer Center Shared Resources > Microscopy Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	22 July 2022
Date Deposited:	26 Jul 2022 22:16
Last Modified:	09 Feb 2024 20:27
PMCID:	PMC9431713
URI:	https://repository.cshl.edu/id/eprint/40688

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