NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens.
The host response against diverse bacterial pathogens involves activation of specialized immune cells and elaboration of pro-inflammatory cytokines that help to coordinate appropriate host defense. Members of the interleukin-1 (IL-1) cytokine family, IL-1beta and IL-18, are central players in this process. Extracellular release of the mature, active form of these cytokines requires their processing by the cysteine protease caspase-1, which therefore serves as a key regulator of the inflammatory response. In addition to its role in secretion of pro-inflammatory cytokines, caspase-1 is also required for a form of cell death, recently termed pyroptosis, that occurs in macrophages infected by certain bacterial pathogens. Caspase-1 itself is synthesized as a pro-enzyme, which must first be activated by autocatalytic cleavage. This activation requires recruitment of caspase-1 into multiprotein complexes known as inflammasomes. The Nod-like receptor (NLR) family of cytosolic proteins play an important role in detecting inflammatory stimuli and subsequently mediate inflammasome assembly. A common feature of NLR proteins that trigger inflammasome assembly in response to bacterial infection is that they appear to sense membrane perturbation or delivery of bacterial components into the cytosol through bacterial pore-forming toxins or bacterial secretion systems. This review will discuss the recent developments regarding caspase-1 activation in response to bacterial infection, cross-talk between caspase-1 and other pathways involved in regulating cell death, and recent findings that a number of bacterial pathogens possess mechanisms to inhibit caspase-1 activation.
Brodsky
Igor E
IE
Yale University School of Medicine, Department of Immunobiology, New Haven, CT 06520, USA. igor.brodsky@yale.edu
Monack
Denise
D
D000818:Animals; D001424:Bacterial Infections / Q000201:enzymology / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000276:immunology*
D053468:CARD Signaling Adaptor Proteins; D061945:Caspase Inhibitors; D020170:Caspase 1