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

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-gamma (IFN gamma) 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 IFN alpha was about fifty-fold less effective than IFN gamma. Conversely, TNF alpha or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFN gamma-activated lung epithelial cells was dependent on IFN gamma signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFN gamma, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFN gamma is a potent enhancer of lung epithelial cell susceptibility to necroptosis.

Automated summary

In this study, the researchers found that interferon-gamma (IFN gamma) can enhance the susceptibility of lung epithelial cells to necroptosis, leading to an accelerated release of damage-associated molecular patterns. They also discovered that the necroptosis effector mixed lineage kinase domain-like protein (MLKL) is predominantly induced by IFN gamma in lung epithelial cells.