Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases

Abstract

The nucleotide-binding domain, leucine-rich repeat (NLR) proteins are a recently discovered family of intracellular pathogen and danger signal sensors. NLRs have emerged as important contributors to innate immunity in animals. The physiological impact of these genes is increasingly evident, underscored by the genetic association of variant family members with an array of inflammatory diseases. The association of mutations in NLR genes with autoinflammatory diseases indicates an important function of these genes in inflammation in vivo. This review summarizes the role of the inflammasome NLR proteins in innate immunity and inflammatory diseases and explores the possible utility of some of these NLRs as pharmacological targets.

FIGURE 1

Domain organization of inflammasome NLRs. NLR proteins have a conserved tripartite structure consisting of an N-terminal effector domain, a central NBD, and a variable number of C-terminal LRRs. Abbreviations not defined elsewhere: BIR, baculovirus inhibitor of apoptosis repeat; FIIND, function to find domain; PYR, pyrin domain.

FIGURE 2

NLR Inflammasomes. In response to PAMPs or DAMPs, the NLRs are activated to form multiprotein caspase-activating platforms referred to as inflammasomes. The NLRP1 inflammasome when activated by MDP or anthrax lethal toxin can recruit procaspase-1 via direct CARD-CARD interactions and cause its autocatalytic cleavage to mature caspase-1. The activated caspase-1 can then process IL-1 β and IL-18 from their inactive proproteins to mature active forms. The NLRP3 inflammasome is activated in response to several PAMPs and DAMPs, including but not restricted to nucleic acids (–15), LPS (13), lipooligosaccharide (29),MDP(30), ATP(17), uric acid crystals (18), hyaluronan and heparan sulfate (31), amyloid- β (20), and asbestos and silica (21, 32). NLRP3forms a multiprotein inflammasome complex with the adaptor protein ASC and procaspase-1. Association of NLRP3 with ASC is required for recruitment of procaspase-1. The CARD domain of ASC is used to recruit procaspase-1 by CARD-CARD interactions, thus leading to the processing of procaspase-1 into active caspase-1. Caspase-1 is in turn critical for the processing and release of IL-1 β and IL-18. The NLRC4 inflammasome is a cytosolic sensor of flagellin and pathogens such as S. typhimurium, S. flexneri, and L. pneumophila (–9, 11, 34). NLRC4 forms a homo-oligomeric inflammasome with caspase-1. The C-terminal, 35-aa fragment of flagellin is sensed by NAIP5 leading to a NAIP5-dependent cell death whereas full-length flagellin induces NAIP5-independent but NLRC4-dependent cell death and IL-1 β release (10). BIR, baculovirus inhibitor of apoptosis repeat; FIIND, function to find domain; PYR, pyrin domain.