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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 5

PTP1B inhibitors attenuated PI3Kγ-mediated CXCR4 signaling.

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PTP1B inhibitors attenuated PI3Kγ-mediated CXCR4 signaling.
(A) Quantita...
(A) Quantitation of MPO from neutrophils isolated from mice treated with vehicle + saline, vehicle + MSI-1436, AZD5069 + MSI-1436, and AZD5069 + saline (n = 5 mice for each group). (B) Percentage of neutrophils, designated as Ly6G+ population, relative to total WBCs, from the indicated treatment groups (n = 5 mice for each group). (C) Immunoblot analyses showing the effect of MSI-1436 on CXCR4 signaling upon CXCL12 stimulation from primary neutrophils isolated from BM. Representative immunoblot of 4 independent experiments. (D) Immunoblot analyses showing the AKT signaling in response to PI3K isoform–specific inhibitors in HeLa, HL-60, and mouse neutrophils. Inhibitors used: α-specific (HS-173, 1 μM); β-specific (GSK2636771, 10 μM); δ-specific (Nemiralisib, 100 nM); γ-specific (Eganelisib, 200 nM); pretreated 1 hour before CXCL12 stimulation. Representative immunoblot of 3 independent experiments. (E) Immunoblot analyses showing the impact of pretreatment with MSI-1436 on AKT signaling in HeLa, HL-60, and mouse primary neutrophils. Representative immunoblot of 3 independent experiments. Data are presented as mean ± SEM. Statistical analysis for A and B by 1-way ANOVA with Tukey’s multiple-comparison test. *P < 0.05, ***P < 0.001, ****P < 0.0001.

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ISSN 2379-3708

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