Pyroptosis: host cell death and inflammation

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Abstract
Life or death of individual cells determines health and disease in multi-celled organisms. Cell death is crucial for organogenesis in utero and successful control of host cell populations in healthy tissues, but can also play a part in disease that occurs in response to toxic insults or microbial infection. The cysteine protease family called caspases is composed of both initiators and effectors, have crucial roles in cell death and drive mechanistically distinct modes of cellular demise. The physiological consequences of cell death are determined by the mechanisms employed, which range from relatively benign cellular destruction to alarm-ringing inflammatory recruitment of additional cells and biochemical processes. Microorganism- and host-derived 'danger' signals stimulate formation of a multiprotein complex, termed the inflammasome, which leads to processing and activation of caspase 1. Active caspase 1 causes pyroptosis and is responsible for proteolytic maturation of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Pyroptosis is characterized by caspase 1-dependent formation of plasma-membrane pores, which leads to pathological ion fluxes that ultimately result in cellular lysis and release of inflammatory intracellular contents. During microbial infection in vivo, caspase 1-dependent processes control pathogen replication, stimulate adaptive immune responses and enhance host survival; however, inappropriate activation of caspase 1 can lead to pathological inflammation. Pathogens have a range of mechanisms for preventing the activation of caspase 1, highlighting its antimicrobial role during infection. Pathogens can directly inhibit caspase 1 activation, induce alternative forms of cell death or regulate production of caspase 1-activating ligands.