Caspase-11 promotes allergic airway inflammation
Zbigniew Zasłona, Ewelina Flis, Mieszko M. Wilk, Richard G. Carroll, Eva M. Pålsson‐McDermott, Mark Hughes, Ciana Diskin, Kathy Banahan, Dylan G. Ryan, Alexander Hooftman, Alicja Misiak, Jay Kearney, Günter Lochnit, Wilhelm Bertrams, Timm Greulich, Bernd Schmeck, Oliver J. McElvaney, Kingston H. G. Mills, Ed C. Lavelle, Małgorzata Wygrecka, Emma M. Creagh, Luke O'neill
Abstract
Abstract Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E 2 (PGE 2 ) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE 2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE 2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE 2 production with indomethacin enhances, whereas the prostaglandin E 1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE 2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.