Inflammasome pathway


Pathway Description

Inflammasomes are innate immune system complexes that regulate the activation of caspase-1 to induce inflammation in response to infectious microbes and molecules derived from host damage. They have been implicated in a variety of inflammatory processes and disorders. They assemble in the cytosol after sensing pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Several varieties have been characterized, which differ in the signals they respond to.Several families of PRRs are key nucleators of inflammasome complexes, including the nucleotide-binding domain, leucine-rich repeat containing proteins (also known as NOD- like receptors, NLRs) and the absent in melanoma 2 (AIM)-like receptors (ALRs) in both mice and humans. Upon sensing pathological stimuli, the relevant NLR or AIM2 can oligomerize with scaffold protein ASC into filamentous form, which binds and activates pro-caspase-1. Active caspase-1 functions to cleave the proinflammatory IL-1 family of cytokines into their bioactive forms, IL-1β and IL-18, and can also cause pyroptosis, a type of inflammatory cell death.

The NLRP3 inflammasome must be primed before activation. Priming involves two distinct steps. First, an NF-κB-activating stimulus, such as LPS binding to TLR4, induces elevated expression of NLRP3 (as well as IL1B), which leads to increased expression of NLRP3 protein. Additionally, priming immediately licenses NLRP3 by inducing its deubiquitination. The adaptor protein ASC must become linearly ubiquitinated and phosphorylated for inflammasome assembly to occur. After priming, canonical NLRP3 inflammasome activation requires a second, distinct signal to activate NLRP3 and lead to the formation of the NLRP3 inflammasome complex. The most commonly accepted activating stimuli for NLRP3 include relocalization of NLRP3 to the mitochondria, the sensation of mitochondrial factors released into the cytosol (mitochondrial ROS, mitochondrial DNA, or cardiolipin), potassium efflux through ion channels, and cathepsin release following destabilization of lysosomal membranes.

In contrast to the diverse stimuli that activate NLRP3 inflammasomes, the NLRC4 inflammasome responds to a more limited set of stimuli. NLRC4 forms a complex with various NAIP proteins, and NLRC4-activating ligands are bound by these NAIP components rather than by NLRC4. In mice, NAIP1 binds the bacterial type III secretory system (T3SS) needle protein. NAIP2 binds the bacterial T3SS rod protein and both NAIP5 and NAIP6 bind bacterial flagellin.

NLRP1 assembles a multimolecular complex inflammsome with caspase-1, caspase-5, ASC, and a triphosphate ribonucleotide. NLRP1 directly binds to ASC, via its pyrin (PYD) domain and directly to caspase-1 via its CARD domain. Activity of the NLRP1 inflammasome is induced by muramyl dipeptide (MDP) and anthrax lethal toxin (mouse NLRP1b). Studies have indicated that NOD2 is needed for in vitro sensing of both MDP and anthrax lethal toxin.

The non-NLR AIM2 can also form a caspase-1-containing inflammasome, but, unlike the NLRs, the HIN- 200 domain of AIM2 can directly bind its stimulus, cytosolic dsDNA, which may be encountered in the cytosol during pathogenic infection. The autoinhibitory conformation of AIM2 is created by interactions of its two domains and relieved by the sugar phosphate backbone of dsDNA. DNA binding displaces the PYD domain, freeing the PYD domain to recruit ASC to the complex.