Human caspase-4 and caspase-5 are potential functional orthologs of mouse caspase-11, which is required for activation of caspase-1 in macrophages in response to certain stimuli. In the Journal of Immunology, Beer and colleagues show that caspase-4 is required for the activation of caspase-1 by the NLRP3 inflammasome and, in turn, for the maturation of pro-IL-1b. Human epidermis has high expression of caspase-4, and ultraviolet irradiation induces the release of caspase-4. Expression and the enzymatic activity of caspase-4 are required for efficient IL-1b secretion, whereas knockdown of caspase-5 has no effect on the secretion of IL-1b from keratinocytes. Caspase-4 interacts with caspase-1 in these cells but not with pro-IL-1b or with the critical inflammasome adaptor ASC. Caspase-4 is also required for activation of the NLRP3 inflammasome in THP-1 mouse macrophages, which suggests that other cells types might also require caspase-4 for the secretion of IL-1b.

J. Immunol. 188, 1992–2000 (2012)