Policing the cytosol—bacterial-sensing inflammasome receptors and pathways

Abstract

Pattern recognition receptors recognize signals originating from pathogens and comprise a large part of the arsenal in innate immune responses. The NOD-like receptors (NLRs) are one particular class of these receptors that survey the cytoplasm for signs of pathogen invasion. Upon detection, they trigger the formation of a macromolecular complex called the inflammasome that is required for elimination of the pathogen, as well as amplifying a pro-inflammatory response. Although the core machinery has been defined, recent data emphasize the complexity of how NLR inflammasomes function. Here, we highlight new discoveries that reveal how precisely fine-tuned NLR inflammasome functions are, and how that may be modulated by antagonistic effects of concomitant inflammasome activation as well as novel regulatory factors.

A Group A Streptococcus ADP-Ribosyltransferase Toxin Stimulates a Protective Interleukin 1β-Dependent Macrophage Immune Response

“…With IL-1β production blocked in Casp1/NRLP3/ASC-deficient macrophages ( Fig. 5D ), the survival advantage of the Δ spyA mutant over the WT GAS strain was eliminated, likely due to a lack of IL-1β to trigger recruitment of antimicrobial effectors or of proinflammatory cytokines to restrict bacterial survival ( 14 , 16 , 17 ).…”

“…Unlike apoptosis, which is activated by a subset of caspases, including caspase-3, the key regulator inducing pyroptosis is caspase-1 ( 15 ). While apoptosis is an “immunologically silent” process marked by formation of membrane-bound apoptotic bodies featuring cytoplasmic and nuclear condensation ( 13 , 16 ), pyroptosis is a proinflammatory process characterized by rapid plasma membrane rupture and release of proinflammatory and immune-boosting cytokines interleukin 1β (IL-1β) and IL-18 ( 16 , 17 ).…”

“…Caspase-1 activity is predominantly regulated by inflammasomes—multimeric complexes comprised of caspase-1, various cytoplasmic pattern recognition receptors, such as NOD-like receptor protein 3 (NLRP3), and an adaptor protein called apoptosis-associated speck-like protein (ASC) ( 16 , 21 ). Inflammasome responses restrict intracellular replication of numerous pathogens ( 13 , 14 , 16 , 17 ), and failure to activate inflammasome oligomerization during microbial infections upon loss of a key inflammasome component(s) severely dampens macrophage killing, allowing accelerated bacterial replication ( 22 , 23 ). Inflammasome- and caspase-1-dependent macrophage cell death is triggered in the presence of “danger signals” from intracellular pathogens such as Shigella , Yersinia , Salmonella , Legionella , and Francisella spp.…”

“…Inflammasome- and caspase-1-dependent macrophage cell death is triggered in the presence of “danger signals” from intracellular pathogens such as Shigella , Yersinia , Salmonella , Legionella , and Francisella spp. ( 14 – 17 ). GAS pore-forming cytolysin streptolysin O (SLO) induces NLRP3 inflammasome-dependent signaling to activate caspase-1 and IL-1β secretion in macrophages ( 24 ), but the impact of this proinflammatory cell death on bacterial clearance and disease pathogenesis has not been analyzed.…”

Revisiting Caspase-11 Function in Host Defense

“…Engagement of NLRP3 and ASC promotes caspase-1 inflammasome activity that leads to maturation of pro-caspase-1, pro-IL-1β and pro-IL-18. Figure modified from (Ng et al, 2013). …”