Abstract
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.
Highlights
Acute respiratory distress syndrome (ARDS) is a form of life-threatening respiratory failure that is associated with high morbidity and mortality [1,2]
We determined whether lung epithelial cells that are pre-activated by pro-inflammatory mediators preferentially undergo necroptosis
The present study provides compelling evidence that IFNγ preferentially among various inflammatory mediators promotes necroptosis in primary alveolar and airway epithelial cells but not in lung microvascular endothelial cells
Summary
Acute respiratory distress syndrome (ARDS) is a form of life-threatening respiratory failure that is associated with high morbidity and mortality [1,2]. ARDS can develop following various types of acute lung injuries (ALI) resulting from pulmonary (e.g., pneumonia, aspiration) or nonpulmonary (e.g., sepsis, pancreatitis, trauma) insults [2]. ARDS affects approximately 3 million patients annually and accounts for 10% of intensive care unit admissions [3]. Due to the ongoing coronavirus disease 2019 (COVID-19) pandemic, the number of patients diagnosed with ARDS/ALI increased substantially [4,5]. ALI/ARDS manifests as hypoxemia, lung edema, decreased lung compliance and diffuse pulmonary infiltrates [1,2,4]. Despite decades of efforts on research, the pathogenesis of ALI/ARDS is not fully elucidated and treatment options are limited as a result. Supportive care with mechanical ventilation remains the mainstay of management for ALI/ARDS [2,4]
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