Journal Article

Caspase-11 promotes allergic airway inflammation

Diskin, Ciana, Wygrecka, Małgorzata, Bertrams, Wilhelm, Zasłona, Zbigniew, Wilk, Mieszko M., Lavelle, Ed C., Flis, Ewelina, Palsson-McDermott, Eva M., Mills, Kingston H. G., Hooftman, Alexander, Greulich, Timm, Banahan, Kathy, Misiak, Alicja, Creagh, Emma M., Hughes, Mark M., O’Neill, Luke A. J., Lochnit, Gunter, Carroll, Richard G., Schmeck, Bernd, McElvaney, Oliver J., Kearney, Jay, Ryan, Dylan G.

2020

Overview

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. Caspase 11 activation involves transcriptional upregulation and proteolytic cleavage. Here the authors show that prostaglandin E 2 prevents caspase-11-mediated pyroptosis, blocking caspase-11 mRNA and protein upregulation in macrophages and in vivo, and that mice lacking caspase-11 are strongly protected from allergic airway inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/21 / 13/31 / 631/250/1932 / 631/250/256 / 64/110 / 692/4017 / 82/1 / Alveoli / Animals / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Asthma / Asthma - immunology / Asthma - pathology / Caspase-1 / Caspase-11 / Caspase-4 / Caspases, Initiator - genetics / Caspases, Initiator - immunology / Caspases, Initiator - metabolism / Cell death / Cells, Cultured / Dinoprostone - metabolism / Drug Synergism / Female / Homology / Humanities and Social Sciences / Humans / Hypersensitivity / Indomethacin / Indomethacin - pharmacology / Inflammation / Lungs / Macrophages / Macrophages - immunology / Mice / Mice, Inbred C57BL / Mice, Knockout / Misoprostol / Misoprostol - pharmacology / multidisciplinary / Prostaglandin E1 / Prostaglandin E2 / Proteolysis / Pyroptosis / Pyroptosis - physiology / Respiratory tract / Respiratory tract diseases / Rodents / Science / Science (multidisciplinary) / Transcription activation