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

Song, Dongyan; Adrover, José 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.

doi:10.1172/jci.insight.158199

Cited by 21 publications

(15 citation statements)

References 86 publications

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“…In addition, glycyrrhizin, the active component of traditional Chinese medicine, reduces neutrophil NETs formation in sepsis by inhibiting the activation of the HMGB1/TLR9/MyD88 (myeloid differentiation primary response 88) pathway ( 286 ). Inhibitors of protein tyrosine phosphatase-1B (PTP1B) reduce neutrophil chemotaxis and NETs formation by inhibiting the PI3γ/AKT/mTOR pathway downstream of CXCR4 signaling ( 306 ). Interestingly, administration of DNase-I-coated melanin-like nanospheres (DNase-I pMNSs) mitigates sepsis-associated NETosis, thereby preventing the further progression of ARDS ( 307 ).…”

Section: Potential Therapeutic Targets For Septic Ardsmentioning

confidence: 99%

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Wang

Zhu²,

Liu³

et al. 2023

Front. Immunol.

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Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.

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Section: Potential Therapeutic Targets For Septic Ardsmentioning

confidence: 99%

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Wang

Zhu²,

Liu³

et al. 2023

Front. Immunol.

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“…The findings presented in this study allow us to explain a long-standing mystery of great mechanistic importance in a widely used model of immune-mediated organ injury; in particular, why 34-1-2S antibody injections (but not injections of other anti-MHC class I antibodies) cause such striking pathophysiology in mice carrying the H-2 d but not H-2 b MHC haplotype (6,19,20,(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). We posit that high affinity binding to multiple MHC class I antigens on the pulmonary endothelium of mice with the H-2 d haplotype facilitates sufficiently dense alloantibody deposition for IgG hexamer assembly to occur.…”

Section: Discussionmentioning

confidence: 92%

IgG hexamers initiate acute lung injury

Cleary,

Seo,

Tian

et al. 2024

Preprint

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Antibodies can initiate lung injury in a variety of disease states such as autoimmunity, transfusion reactions, or after organ transplantation, but the key factors determining in vivo pathogenicity of injury-inducing antibodies are unclear. A previously overlooked step in complement activation by IgG antibodies has been elucidated involving interactions between IgG Fc domains that enable assembly of IgG hexamers, which can optimally activate the complement cascade. Here, we tested the in vivo relevance of IgG hexamers in a complement-dependent alloantibody model of acute lung injury. We used three approaches to block alloantibody hexamerization (antibody carbamylation, the K439E Fc mutation, or treatment with domain B from Staphylococcal protein A), all of which reduced acute lung injury. Conversely, Fc mutations promoting spontaneous hexamerization made a harmful alloantibody into a more potent inducer of acute lung injury and rendered an innocuous alloantibody pathogenic. Treatment with a recombinant Fc hexamer "decoy" therapeutic protected mice from lung injury, including in a model with transgenic human FCGR2A expression that exacerbated pathology. These results indicate a direct in vivo role of IgG hexamerization in initiating acute lung injury and the potential for therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases.

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“…The first thing that comes to mind is that PI3Kγ has phosphoinositide kinase activity which phosphorylates phosphatidylinositol 2 phosphate PIP2 to phosphatidylinositol 3 phosphate PIP3; phosphorylation of PIP3 recruits AKT with a PH structural domain and activates downstream signaling. Previous studies indicated that PI3Kγ drived NETs formation dependent on the activation of AKT signaling 40, 44 . However, they did not perform rescue experiments to prove that PI3Kγ regulates NETs formation through PI3K/AKT.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the identification of upstream regulators of NETs is crucial for AAA treatment. Previous studies have shown that inhibition of PI3Kγ 27 / 50 promotes neutrophil senescence and reduces NETs, which in turn treats acute lung injury 40 . PI3Kγ depletion protects against microscopic polyangiitis by inhibiting NETs formation 26 .…”

Section: Discussionmentioning

confidence: 99%

PI3Kgamma promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm

Xiong,

Liu,

Liu

et al. 2024

Preprint

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Background: Abdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases while currently lacks effective drug treatment. NETs formation has been proved to be crucial trigger of AAA, so finding its upstream regulatory targets is the key to discovering therapeutic agents for AAA. Methods and Results: we reveal that PI3Kγ (PI3Kγ) is an upstream signal that regulates NETs formation. Inhibition of PI3K? reduces the expression of NETs and reduces inflammation in the aortic wall, thereby significantly ameliorating AAA. However, the mechanism of NETs formation regulated by PI3Kγ has not been fully elucidated. Using isolated bone marrow neutrophils, we show that PI3Kγ deficiency inactivates the noncanonical pyroptosis pathway (Capase11/GSDMD) to inhibit NETs expression, and subsequently found that PI3Kγ regulation of noncanonical pyroptosis via anchoring PKA is dependent on cAMP/PKA signaling, but not on classical PI3K/AKT signaling. Conclusions: Our research uncovers the role and mechanism of PI3Kγ in AAA development and provides insights into AAA therapy from the perspective of NETs formation.

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

Cited by 21 publications

References 86 publications

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

IgG hexamers initiate acute lung injury

PI3Kgamma promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm

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