Moreover, it seems that caspase-11 also MG 132 regulates the cell death mechanism known as pyroptosis, a crucial defense mechanism against certain pathogens

escaping phagosome–lysosome fusion [4]. In this review, we will discuss the latest studies that highlight the emerging importance of caspase-11 driving the noncanonical inflammasome pathway and consider the implications of their conclusions. Murine caspase-11, also known as Ich-3 or caspase-4, is a member of the caspase-1 subfamily of proteases [5], sharing 46% identity with murine caspase-1. In humans, the ortholog of mouse caspase-11 may be either caspase-4 or caspase-5, based on amino acid sequence homology; however, only caspase-5 seems to be regulated in a similar way to murine caspase-11 in response to extracellular stimuli, such as lipopolysaccharide (LPS) and interferons [6]. Caspase-11 is synthesized as 43-kDa and 38-kDa precursors, but in contrast to other caspases, procaspase-11 expression requires inflammatory stimulation. Administration of LPS to mice induces rapid protein expression of procaspase-11

in thymus, spleen, liver, lung [5], and, in particular, in splenic macrophages and B cells [7]. As well as the purified form of LPS, whole Gram-negative bacteria (Vibrio cholerae, flagellin-deficient Salmonella enterica serovar Typhimurium (ΔFlag Salmonella), Escherichia coli, enterohemorrhagic E. coli (EHEC), Legionella pneumophila, Citrobacter rodentium), all of whose outer membranes contain LPS, can induce procaspase-11 expression in macrophages [3, 8-10], while Gram-positive

bacteria cannot [9]. Some of these pathogens activate primarily caspase-1 by the canonical MAPK inhibitor pathway via NLRC4 (wild-type Salmonella and Legionella) or NLRP3 (V. cholerae) [11-13]. As LPS is specifically detected by Toll-like Dichloromethane dehalogenase receptor (TLR) 4, researchers began to interrogate this pathway. It was shown that induction of procaspase-11 expression was delayed in Myd88−/− macrophages infected with ΔFlag Salmonella, although procaspase-11 processing itself remained intact [8]. TRIF is required for the processing of procaspase-11 into the cleaved caspase-11 forms (∼26–30 KDa) (Table 1) [8, 9]. However, the role of TRIF in procaspase-11 expression remains controversial. In two independent studies, it was shown that procaspase-11 upregulation was reduced in Trif−/− macrophages infected with C. rodentium [14], E. coli [14], and EHEC [9, 14]. In two other studies, although procaspase-11 induction was delayed in macrophages after ΔFlag Salmonella infection, the protein levels were maintained [8, 10]. These observations indicate that the role of TRIF in procaspase-11 induction may be context dependent. So how does stimulation of the TRIF pathway by LPS from Gram-negative bacteria mechanistically link to capase-11 production? A series of observations suggest that IFN-mediated pathways downstream of TRIF are key drivers of noncanonical inflammasome activation.