Abstract
Caspase-1, formerly known as interleukin (IL)-1-converting enzyme is best established as the protease responsible for the processing of the key pro-inflammatory cytokine IL-1β from an inactive precursor to an active, secreted molecule. Thus, caspase-1 is regarded as a key mediator of inflammatory processes, and has become synonymous with inflammation. In addition to the processing of IL-1β, caspase-1 also executes a rapid programme of cell death, termed pyroptosis, in macrophages in response to intracellular bacteria. Pyroptosis is also regarded as a host response to remove the niche of the bacteria and to hasten their demise. These processes are generally accepted as the main roles of caspase-1. However, there is also a wealth of literature supporting a direct role for caspase-1 in non-infectious cell death processes. This is true in mammals, but also in non-mammalian vertebrates where caspase-1-dependent processing of IL-1β is absent because of the lack of appropriate caspase-1 cleavage sites. This literature is most prevalent in the brain where caspase-1 may directly regulate neuronal cell death in response to diverse insults. We attempt here to summarise the evidence for caspase-1 as a cell death enzyme and propose that, in addition to the processing of IL-1β, caspase-1 has an important and a conserved role as a cell death protease.
Highlights
Caspy activity is activated by oligimerisation of the zebrafish orthologue of ASC and induces apoptosis when expressed in mammalian 293 T cells.[45]
Infection of seabream macrophages with S. typhimurium induces a caspase-1-dependent pyroptotic cell death, and caspase-1independent processing and secretion of IL-1b.49. These data suggest that the association between caspase-1 activation and IL-1b developed later in evolution, further suggesting a conserved role for caspase-1 in cell death (Figure 2)
In this way caspase-1 could drive an IL-1dependent inflammation across all vertebrate classes
Summary
Have the non-caspase-1-dependent mechanisms of IL-1b secretion in sterile inflammation been underestimated?. In zebrafish (Danio rerio) two orthologues of caspase-1 have been identified, caspy[1] and caspy[2], as have ASC- and NLRlike molecules.[45,46] Caspy activity is activated by oligimerisation of the zebrafish orthologue of ASC and induces apoptosis when expressed in mammalian 293 T cells.[45] YVAD protects zebrafish embryos from camptothecin-induced cell death.[47] Seabream (Sparus aurata L) express caspase-1, and its activity is effectively blocked by YVAD.[48] Classical DAMPs that activate caspase-1 in mammalian cells such as ATP and mono sodium urate do not induce activation of caspase-1 in seabream macrophages.[49] infection of seabream macrophages with S. typhimurium induces a caspase-1-dependent pyroptotic cell death, and caspase-1independent processing and secretion of IL-1b.49 These data suggest that the association between caspase-1 activation and IL-1b developed later in evolution, further suggesting a conserved role for caspase-1 in cell death (Figure 2). Organotypic brain slices Cortical neuron cultures Cell death, mortality in vivo Neocortex
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