Caspase-11 promotes allergic airway inflammation

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.

• Zaslona, 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.