Abstract
Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are activated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. In addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory mediators, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.
Highlights
Inflammasomes are multiprotein platforms containing specialized cytosolic sensors for a wide range of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) that are able to activate the inflammatory caspase-1 and caspase-11 in a manner dependent or independent of adaptor molecules [1,2,3,4]
The members of the NOD-like receptors (NLR) family contain three domains: a central NBD that is responsible for protein oligomerization and common to all members; a C-terminal region composed of LRR sequences that are supposed to sense PAMPs or DAMPs; and an N-terminal portion that is responsible for the specificity of their molecular interactions and, their effector functions
We recently reported that the activation of macrophages with purified flagellin inserted into lipidic vesicles induced IL-1α secretion in a manner partially dependent on caspase-1 and cathepsin B [27]
Summary
Inflammasomes are multiprotein platforms containing specialized cytosolic sensors for a wide range of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) that are able to activate the inflammatory caspase-1 and caspase-11 (caspase-4 in humans) in a manner dependent or independent of adaptor molecules [1,2,3,4]. A study conducted in vivo demonstrated that the NLRC4-dependent flagellin-mediated lysis of bacteria-containing macrophages results in the early loss of the intracellular replication niche and creates an inflammatory milieu with the recruitment of effector cells to the infection site, which are involved in pathogen clearance [32]. The possible targets of caspase-1 and caspase-11 mobilized during pyroptosis www.frontiersin.org remain unidentified, the studies involving NAIP/NLRC4 hugely contribute to the idea that this inflammatory form of cell death is an important effector mechanism against infections. The induction of Tregs and Th17 could impair the immune response against tumor cells, it is reasonable to consider that the activation of Th1 and cytotoxic CD8 T cells by IL-1β and IL-18 may be beneficial to the host [72, 73]
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