In general, the pathogen-associated molecular patterns (PAMPs) recognized by NLRs and TLRs are vital for microbial survival, representing either nucleic acid structures unique to microbes or cell wall components alien to mammalian cells

In general, the pathogen-associated molecular patterns (PAMPs) recognized by NLRs and TLRs are vital for microbial survival, representing either nucleic acid structures unique to microbes or cell wall components alien to mammalian cells. The bipartite adaptor protein ASC plays a central role in the interaction between NLRs and caspase-1 in each of these inflammasome complexes. in large cytosolic protein complexes termed inflammasomes. Most inflammasomes contain a member of the nucleotide binding and oligomerization domain (NOD)-like receptor (NLR) family. These proteins are thought to function as sensors that detect conserved microbial components in intracellular compartments, similar to the role of mammalian Toll-like receptors (TLRs) at the cell surface and within endosomes[2]. NLRs share a domain organization that usually includes (1) an amino-terminal proteinprotein interaction domain such as a CARD or pyrin domain; (2) an intermediary NACHT domain that is required for nucleotide binding and self-oligomerization; and (3) a variable number of carboxy-terminal leucine-rich repeat (LRR) motifs involved in sensing pathogen molecules. In general, the pathogen-associated molecular patterns (PAMPs) recognized by NLRs and TLRs are vital for microbial survival, representing either nucleic acid structures unique to microbes or cell wall components alien to mammalian cells. The bipartite adaptor protein ASC plays a central role in the interaction between NLRs and caspase-1 in each of these inflammasome complexes. As a consequence, caspase-1 activation and the production of IL-1 and IL-18 are abolished in ASC-deficient macrophages that are infected with intracellular bacteria or stimulated with a combination of microbial ligands and ATP[3]. ASC has a specific role in caspase-1 activation because secretion of the cytokines TNF- and IL-6 is not affected by ASC deficiency. Genetic studies in mice suggest that at least four inflammasomes of distinct composition are formed in vivo in a stimulus-dependent manner (Figure 1): the IPAF inflammasome[3][5], the NALP1 inflammasome[6], the Cryopyrin/NALP3 inflammasome[7][9], and a fourth inflammasome triggered byFrancisella tularensisinfection[8],[10]. Biochemical studies suggested the existence of an additional inflammasome containing NALP2[11],[12], although specific ligands for this inflammasome remain to be identified. In addition to these NLRs, the HIN-200 protein absent in melanoma 2 (AIM2) was recently shown to trigger caspase-1 activation in response to cytoplasmic double-stranded DNA (dsDNA)[13][16]. == Figure 1. Stimuli and composition of distinct inflammasomes. == The NLR proteins NALP1b, Cryopyrin/NALP3, and IPAF and the HIN-200 protein AIM2 assemble a caspase-1 activating inflammasome complex in response to specific microbial or bacterial factors. The murine NALP1b inflammasome recognizes the cytosolic presence of anthrax LT. The Cryopyrin/NALP3 inflammasome recognizes multiple PAMPs in combination with Rabbit Polyclonal to PAK2 Benzathine penicilline ATP or nigericin, as well as Benzathine penicilline crystalline substances including MSU, Benzathine penicilline silica, and asbestos particles. The IPAF inflammasome sensesSalmonellaandLegionellaflagellin and a yet unidentifiedShigella flexnericompound, which all access the cytosol through a type III or IV secretion system. Cytosolic PAMPs may trigger assembly of a particular inflammasome complex by causing modifications in unknown host factors (X, Y, Z) that are monitored by specific NLR proteins. In contrast, AIM2 directly binds dsDNA in the cytosol to induce caspase-1 activation. The CARD/pyrin-containing adaptor protein ASC is essential for all these inflammasome complexes, although its role in the NALP1b inflammasome remains to be formally established. Once activated, caspase-1 processes the IL-1 and IL-18 precursors into the mature cytokines, which are secreted through an unknown mechanism. == The IPAF Inflammasome == Caspase-1 activation is largely abolished in IPAF-deficient macrophages infected withSalmonella typhimurium[3][5],Legionella pneumophila[17],[18],Pseudomonas aeruginosa[19][21], orShigella flexneri[22]. Bacterial flagellin, which typically is translocated into the cytosol by a bacterial secretion system (type III forS. typhimuriumandP. aeruginosa; type IV forL. pneumophila), was identified as the bacterial compound that is sensed by IPAF.S. flexnerilacks flagellin, however, so the nature of theS. flexnerifactor that is sensed by IPAF is unknown. Nevertheless, the finding that recombinant purified flagellin induces IPAF-dependent caspase-1 activation when delivered to the cytosol, either using pore-forming proteins or upon transfection with cationic lipids, indicates that cytosolic flagellin is sufficient for IPAF activation regardless of its delivery mechanism[4],[5],[23]. Interestingly, the extracellular flagellin receptor TLR5 is not required for IPAF-mediated detection of cytosolic flagellin and the subsequent activation of caspase-1[4],[5], suggesting that TLR5 and IPAF have evolved to control distinct signalling pathways (NF-B activation and caspase-1 activation, respectively) when the host is infected Benzathine penicilline with intracellular pathogens. == The NALP1 Inflammasome == TheBacillus anthracislethal toxin (LT) consists of a pore-forming protective antigen (PA) subunit and a metalloprotease subunit lethal factor (LF). PA allows delivery of LF into the cytosol of infected cells[24]. Macrophages from C57BL/6J and multiple other inbred mice strains are resistant to LT-induced death, whereas 129/S1 macrophages are highly susceptible. Mutations in Benzathine penicilline theNalp1bgene were identified as the key determinant of LT susceptibility in mice[6]. Five distinctNalp1balleles were identified in 18 mouse strains analyzed, demonstrating the extremely polymorphic nature of theNalp1bgene[6]. Two alleles were found in the susceptible mouse strains, whereas the remaining three alleles correlated with LT resistance. In addition, morpholinos targeting NALP1b rendered LT-sensitive macrophages resistant to.