Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders. In this study, to evaluate the relationship between mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome activation in allergic asthma, we used a newly developed mitochondrial ROS inhibitor, NecroX-5. NecroX-5 reduced the increase of mitochondrial ROS generation in airway inflammatory cells, as well as bronchial epithelial cells, NLRP3 inflammasome activation, the nuclear translocation of nuclear factor-κB, increased expression of various inflammatory mediators and pathophysiological features of allergic asthma in mice. Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice. These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.

Melanoma is an aggressive and drug-resistant cancer in need of improved therapeutic strategies. Restored expression of transcriptionally silenced genes is a potential approach, but it is limited by the genetic diversity of the melanoma tumors. The atypical heat shock protein H11/HspB8 has kinase activity and is silenced in melanoma through aberrant DNA methylation. We report that its restored expression induces the death of genetically diverse melanoma lines and inhibits tumor growth through the activation of novel TAK1-dependent death pathways. These include (i) caspase-1 activation independent of the inflammasome through upregulation of apoptosis-associated speck-like protein containing a CARD (ASC), (ii) Beclin-1 upregulation through phosphorylation of mammalian target of rapamycin (mTOR) at S2481 and (iii) apoptosis caused by caspase-1-mediated Beclin-1 cleavage. These data extend current understanding of cell death-associated functions, underscore the strong therapeutic promise of H11/HspB8 and identify TAK1 as a potential intervention target in melanoma.