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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DOI: 10.1172/jci.insight.158199


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: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle > Neutrophil extracellular traps
diseases & disorders > viral diseases > coronavirus > covid 19
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL labs > Janowitz lab
CSHL labs > Lyons lab
CSHL labs > Tonks lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 22 July 2022
Date Deposited: 26 Jul 2022 22:16
Last Modified: 26 Jul 2022 22:16

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