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Inflammasome Signaling Pathway

The innate immune system works as the first line of defense in protection from pathogens and host-derived signals of cellular distress. As an essential component of the innate immune response, inflammasomes can response to a wide range of physiological and pathogenic stimuli and play an important role in the clearance of pathogens or damaged cells. Inflammasomes are large multimeric complexes typically formed of a cytosolic pattern recognition receptor (specifically a nucleotide-binding domain and leucine-rich-repeat [NLR] or a melanoma 2 [AIM2]-like receptor [ALR] family member), and a bipartite adaptor protein (ASC), and an effector caspase pro-caspase-1.

Assembly of inflammasome complexes is dependent on cytosolic sensing of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) that gain access to the cytosol. Upon detecting specific stimuli, the activated receptor nucleates ASC which is an apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD). Nucleated ASC sequentially recruits pro-caspase-1, which undergoes autocatalytic cleavage to produce the active subunits p10/p20 tetramer. Active caspase-1 can then proteolytically process cytokines pro-IL-1β and pro-IL-18, inducing the generation of the mature biologically active cytokines, as well as the initiation of an inflammatory form of cell death known as pyroptosis by autocatalysis and activation.

Several distinct inflammasomes have been identified and the molecular composition of inflammasome complexes is stimulus dependent. The NLR family can be subdivided into NLRP or NLRC depending on whether the N terminus contains a pyrin or caspase activation and recruitment domain (CARD), respectively. NLR family members have been well established as NLRs capable of forming inflammasomes, such as NLRP1, NLRP3, and NLRC4. Among them, the NLRP3 inflammasome complex is the most characterized and can be activated in response to the widest array of stimuli. The NLRP3 inflammasome is activated in a two-step process, as in most cell types NLPR3 must be primed before activation. First, PAMP- or DAMP-mediated activation of Toll-like receptor or cytokine receptor triggers the activation of NF-κB signaling or AP-1 signaling through p38 or JNK pathway, resulting in elevated expression of NLRP3, pro-IL-1β, and pro-IL-18 proteins (priming step, Signal 1). Additionally, priming immediately licenses NLRP3 by inducing its deubiquitination. Next, indirect activation of NLRP3 occurs by a multitude of signals, leading to the assembly of the NLRP3 inflammasome complex activation of caspase-1 (Signal 2). The most commonly accepted activating stimuli for NLRP3 include whole pathogens, PAMPs/DAMPs, potassium efflux through ion channels, lysosomal-damaging environmental factors (uric acid, silica, alum) and endogenous factors (amyloid-β, cholesterol crystals), and mitochondrial factors released into the cytosol (mitochondrial ROS, mitochondrial DNA, or cardiolipin).

In addition, other NLP members and AIM2 inflammasome are activated by more direct means: muramyl dipeptide (MDP) and anthrax toxin activate NLRP1. Lethal toxin is produced by Bacillus anthrax, it comprises protective antigen, cell-binding protein, oedema factor and lethal factor. The protective antigen forms pores in the host cell membrane that translocate the lethal factor to the cytosol and cleaves NLRP1b at an N-terminal site, leading to the induction of inflammasome activation. NLRC4 responds to bacterial flagellin and multiple components of conserved type III secretion systems (T3SSs). These distinct ligands are detected apoptosis inhibitory proteins (NAIPs) rather than NLRC4. NAIPs, belonging to NLR family, act as sensors to initialize the activation of NLRC4 inflammasome. Unlike NLR inflammasomes, CARD domain is absent in AIM2 and hence require recruitment of ASC through pyrin domain. Double-stranded DNA (dsDNA) activates the AIM2 complex, as the HIN-200 domain of which can directly bind cytosolic dsDNA, making it an important regulator in immune responses after infection with various viral and bacterial infectious agents. Notably, the recognition of dsDNA by AIM2 is independent of the origin or sequence of dsDNA, but instead requires a minimum sequence length of 80 base pairs for optimal inflammasome activation.

Inflammasome activation is a key function mediated by the innate immune system in response to harmful stimuli, such as pathogens, dead cells or irritants. However, overt activation of inflammasomes may also lead to a variety of autoinflammatory and autoimmune diseases, including neurodegenerative diseases (such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease) and metabolic disorders (such as atherosclerosis, obesity and type II diabetes).

References:

  • Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature medicine. 2015 Jul 1;21(7):677-87.
  • Rathinam VA, Fitzgerald KA. Inflammasome complexes: emerging mechanisms and effector functions. Cell. 2016 May 5;165(4):792-800.
  • Lamkanfi M. Emerging inflammasome effector mechanisms. Nature Reviews Immunology. 2011 Mar 1;11(3):213-20.
  • Sharma D, Kanneganti TD. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J Cell Biol. 2016 Jun 20;213(6):617-29.
  • Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nature reviews Immunology. 2016 Jul 1;16(7):407-20.

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