Caspase-11 promotes allergic airway inflammation

Zasłona, Z., Flis, E., Wilk, M.M., Carroll, R.G., Palsson-McDermott, E.M., Hughes, M.M., Diskin, C., Banahan, K., Ryan, D.G., Hooftman, A., Misiak, A., Kearney, J., Lochnit, G., Bertrams, W., Greulich, T., Schmeck, B., McElvaney, O.J., Mills, K.H.G., Lavelle, E.C., Wygrecka, M., Creagh, E.M. & O'Neill, L.A.J., Caspase-11 promotes allergic airway inflammation, 2020, Nature Communications;

Abstract

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 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 PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 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 PGE2 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