Key Points
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Caspase 1 and caspase 11 control both the release of inflammatory cytokines and the execution of pyroptosis upon inflammasome activation. Caspase 1 can be activated independently of caspase 11 in response to canonical NLRP3, NLRC4 and AIM2 inflammasome triggers. Caspase 1 activation is dependent on caspase 11 in response to 'non-canonical' triggers, such as Gram-negative bacteria and the intracellular delivery of LPS into cells through various experimental means.
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Infection with clinically significant Gram-negative bacteria triggers caspase 11 activation via an undefined non-canonical inflammasome pathway that is independent of NLRP3, NLRC4 and AIM2. Caspase 11, as well as human caspase 4 and caspase 5, bind to LPS with high specificity and affinity, and trigger this pathway. LPS-induced lethality in mice, which has long been ascribed to caspase 1, is rather mediated by caspase 11.
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Earlier studies revealed a suppressive function for the apoptosis 'initiator' caspase 8 in inflammation in vivo. New studies show that caspase 8 is integrated into inflammatory signalling pathways downstream of RIG-I, dectin 1 and TLR4, in which caspase 8 either facilitates or attenuates inflammation. Future studies will undoubtedly elucidate the full impact of caspase 8 activity on inflammation.
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RHIM domain interactions between RIPK3 and TRIF downstream of TLR3 and TLR4, or RIPK3 and DAI, trigger necrotic cell death that is suppressed by the activity of caspase 8 and independent of the kinase activity of RIPK1.
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RIPK1 deubiquitylation triggers spontaneous assembly of a 2 MDa ripoptosome, with a RIPK1−FADD−caspase 8 module at its core. The ripoptosome is recruited to TLR3 via RHIM domain interactions between TRIF and RIPK1. The presence of long and short isoforms of FLICE-like inhibitory protein (FLIPL and FLIPS, respectively) within this complex regulates caspase 8 activity and dictates either cellular survival and signalling, or cell death. The decision whether cells die by apoptosis or necroptosis is determined by a balance between the activities of caspase 8 and the master orchestrator of necroptosis, RIPK3.
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FADD and caspase 8 have crucial effects on canonical and non-canonical inflammasome pathways, the activation of which is closely tied to both inflammation and cell death. The details of how these apoptosis-associated molecules are integrated into inflammasome pathways and their impact on inflammasome function continue to unfold.
Abstract
Historically, cell death and inflammation have been closely linked, but the necessary divergence of the fields in the past few decades has enriched our molecular understanding of the signalling pathways that mediate various programmes of cell death and multiple types of inflammatory responses. The fields have now come together again demonstrating a surprising level of integration. Intimate interconnections at multiple levels are revealed between the cell death and inflammatory signal transduction pathways that are mobilized in response to the engagement of pattern recognition receptors during microbial infection. Molecules such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, FAS-associated death domain protein (FADD), FLICE-like inhibitory protein (FLIP) and caspase 8 — which are associated with different forms of cell death — are incorporated into compatible and exceedingly dynamic Toll-like receptor, NOD-like receptor and RIG-I-like receptor signalling modules. These signalling modules have a high capacity to switch from inflammation to cell death, or a programmed execution of both, all in an orchestrated battle for host defence and survival.
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Change history
27 August 2014
Previously, the author biography incorrectly stated that the author received the "MSSM Faculty Council Award for Academic Excellence in 2011". This has now been corrected to "ISMMS Faculty Council Award for Academic Excellence in 2011".
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Acknowledgements
J.M.B. is supported by the US National Institutes of Health (grants AI095245 and DK072201), the Burroughs Wellcome Trust Fund, the American Cancer Society, the Leukemia and Lymphoma Society, and the Irma-Hirschl and Monique Weill-Caulier Charitable Trust Funds.
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Blander, J. A long-awaited merger of the pathways mediating host defence and programmed cell death. Nat Rev Immunol 14, 601–618 (2014). https://doi.org/10.1038/nri3720
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DOI: https://doi.org/10.1038/nri3720
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