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Under threat of pathogen invasion, timely initiation of inflammation is a critical first step in generating a protective immune response. One major obstacle for the immune system is discriminating pathogenic microbes from non-pathogenic microbiota. Some members of the nucleotide-binding oligomerization domain-like receptor (NLR) family of pattern recognition receptors accomplish this distinction based on localization—typically, only pathogens deliver NLR ligands into the cytosol, where these receptors are localized. Ultimately, these NLRs initiate assembly of an inflammasome complex that activates the proteases caspase-1 and caspase-11. These caspases were originally identified for their role in IL-1β processing and release but are now known to direct additional important cellular processes during infection, inflammatory disorders, and response to injury. In this brief review, we enumerate these emerging pathways (Figure 1) and highlight their roles in disease.    Figure 1  Effector mechanisms of pyroptosis.     IL-1β and IL-18 The proinflammatory cytokines IL-1β and IL-18 were the earliest studied caspase-1 substrates. IL-1β directs diverse processes, including extravasation, cell proliferation and differentiation, cytokine secretion, angiogenesis, wound healing, and pyrexia [1]. IL-18 is best known for stimulating NK and T cells to secrete IFN-γ, another broad-activity cytokine. Production of these potent cytokines is tightly regulated: expression requires NF-κB signaling, biological activity requires cleavage of a pro-domain by caspase-1, and secretion is also directed by caspase-1 [1]. Mice unable to signal via IL-1β and IL-18 are more susceptible to several diverse pathogens, including Shigella, Salmonella, Candida albicans, Staphylococcus aureus, and influenza virus [1]. However, caspase-1−/− mice are more susceptible to some infections than IL-1β−/−IL-18−/− mice [2], underscoring the importance of additional caspase-1 substrates that alter the immune response.

Burning Down the House: Cellular Actions during Pyroptosis