its CARD-dependent polymerization into discrete caspase 1 filaments. This aggregation seems to trigger the autocleavage of pro-caspase 1, which releases the active caspase 1 fragment from its autoinhibitory domains. Active caspase 1 then carries out the ATP-dependent proteolytic processing of pro-inflammatory cytokines, particularly IL-1β and IL-18, into their active forms (see Fig. 3.19). Caspase 1 activation also induces a form of cell death called pyroptosis (‘fiery death’) through an unknown mechanism that is associated with inflammation because of the release of these pro-inflammatory cytokines upon cell rupture.
For inflammasome activation to produce inflammatory cytokines, a priming step must first occur in which cells induce and translate the mRNAs that encode the pro-forms of IL-1β, IL-18, or other cytokines. This priming step can result from TLR signaling, which may help ensure that inflammasome activation proceeds primarily during infections. For example, the TLR-3 agonist poly I:C (see Section 3-5) can be used experimentally to prime cells for subsequent triggering of the inflammasome.
Several other NLR family members form inflammasomes with ASC and caspase 1 that activate these pro-inflammatory cytokines. NLRP1 is highly expressed in monocytes and dendritic cells and is activated directly by MDP, similar to NOD2, but can also be activated by other factors. For example, Bacillus anthracis expresses an endopeptidase, called anthrax lethal factor, which allows the pathogen to evade the immune system by killing macrophages. Lethal factor does this by cleaving NLRP1, activating an NLRP1 inflammasome and inducing pyroptosis in the infected macrophages. NLRC4 acts as an adaptor with two other NLR proteins, NAIP2 and NAIP5, that serve to detect various bacterial proteins that enter cells through specialized secretion systems used by pathogens to transport materials into or access nutrients from host cells. One such protein, PrgJ, from the pathogen Salmonella typhimurium, is a component of the type III secretion system (T3SS), a needle-like macromolecular complex. Upon infection of host cells by Salmonella, PrgJ enters the cytoplasm and is recognized by NLRC4 functioning together with NAIP2. Extracellular bacterial flagellin is recognized by TLR5, but flagellin may also enter host cells with PrgJ via the T3SS, and in this case can be recognized by NLRC4 in conjunction with NAIP5. Some NLR proteins may negatively regulate innate immunity, such as NLRP6, since mice lacking this protein exhibit increased resistance to certain pathogens. However, NLRP6 is highly expressed in intestinal epithelium, where it appears to play a positive role in promoting normal mucosal barrier function and is required for the normal secretion of mucus granules into the intestine by goblet cells. NLRP7, which is present in humans but not mice, recognizes microbial acylated lipopeptides and forms an inflammasome with ASC and caspase 1 to produce IL-1β and IL-18. Less is known about NLRP12, but like NLRP6, it initially was proposed to have an inhibitory function. Subsequent studies of mice lacking NLRP12 suggest it has a possible role in the detection of and response to certain bacterial species, including Yersinia pestis, the bacterium that causes bubonic plague, although the basis of this recognition is still unclear.