Extracellular adenosine 5′-triphosphate in pulmonary disorders

Pelleg, Amir

doi:10.1016/j.bcp.2020.114319

Cited by 22 publications

(13 citation statements)

References 127 publications

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“…The inflammatory functions of HMGB1 are mediated through the receptor for advanced glycation end products (RAGE), TLR2, TLR4, and TLR9 [44,45]. ATP activates P2 purinergic receptors, through which it is involved in multiple pulmonary disorders [46,47], while dsDNA including mitochondrial DNA triggers an innate immune response through DNA sensors [48,49]. On the basis of these results, we posit that enhanced necroptosis in IFNγ-activated lung epithelial cells not only promotes cell death but also accelerates the release of immune-stimulatory DAMPs, through which they may contribute to the exaggerated tissue injury, inflammation and lung dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Qin

Shetty

Tucker

et al. 2022

Cells

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Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury (ALI). As ALI is often associated with a cytokine storm, we determined whether pro-inflammatory cytokines modulate the susceptibility of lung cells to necroptosis and which mediators dominate to control necroptosis. In this study, we pretreated/primed mouse primary lung epithelial and endothelial cells with various inflammatory mediators and assessed cell type-dependent responses to different necroptosis inducers and their underlying mechanisms. We found that interferon-γ (IFNγ) as low as 1 ng/mL preferentially promoted necroptosis and accelerated the release of damage-associated molecular patterns from primary alveolar and airway epithelial cells but not lung microvascular endothelial cells. Type-I IFNα was about fifty-fold less effective than IFNγ. Conversely, TNFα or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFNγ-activated lung epithelial cells was dependent on IFNγ signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFNγ, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFNγ is a potent enhancer of lung epithelial cell susceptibility to necroptosis.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Qin

Shetty

Tucker

et al. 2022

Cells

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“…CD73 is a transmembrane protein that plays an important pathophysiological role in conversion of AMP to adenosine. Recent studies have demonstrated that CD73 has an important role in pulmonary disease depend on types of injury [27]. It is unclear whether CD73 de ciency plays an important role in airway in ammation induced by A.f.…”

Section: Discussionmentioning

confidence: 99%

Adenosine metabolism inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus

liu

Wang

Zhang

et al. 2023

Preprint

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Background: Given that severe inflammatory reaction is an important manifestation of asthma, it would be helpful to understand the pathological mechanism of asthma to determine the endogenous anti-inflammatory events of asthma. Recent studies have found that energy metabolites in the body are related to some inflammatory diseases, but little is known about their role in asthma. Method: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene–knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5’-(α, β-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. Result: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic destruction of CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. Conclusion: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

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“…In fact, CD73 modifies the recruitment and bactericidal function of PMNs, thereby providing a therapeutic strategy for regulating potentially harmful inflammatory host responses during Gram-positive bacterial pneumonia. Similarly, CD73-derived adenosine is an important regulator of the inflammatory/immune response in animal models of allergic airway inflammation [ 57 , 58 ]. As demonstrated by the experimental data, both the upregulation of CD73 expression and activity in the lung of OVA-sensitized WT mice represent a self-protective mechanism that may regulate lung injury and tissue damage caused by inflammation [ 59 , 60 ].…”

Section: Cd73 Exerts Bidirectional Modulatory Effects On Lung Injurymentioning

confidence: 99%

CD73: Friend or Foe in Lung Injury

Shi

Zhang

et al. 2023

IJMS

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Ecto-5′-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to limit an excessive immune response in many pathophysiological events, such as lung injury induced by a variety of contributing factors. Multiple lines of evidence suggest that the location of CD73, in proximity to adenosine receptor subtypes, indirectly determines its positive or negative effect in a variety of organs and tissues and that its action is affected by the transfer of nucleoside to subtype-specific adenosine receptors. Nonetheless, the bidirectional nature of CD73 as an emerging immune checkpoint in the pathogenesis of lung injury is still unknown. In this review, we explore the relationship between CD73 and the onset and progression of lung injury, highlighting the potential value of this molecule as a drug target for the treatment of pulmonary disease.

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Extracellular adenosine 5′-triphosphate in pulmonary disorders

Cited by 22 publications

References 127 publications

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Adenosine metabolism inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus

CD73: Friend or Foe in Lung Injury

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