[2][3][4] The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines.
[4][6] The germline-encoded PRRs that drive inflammasome formation consist of NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors), AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16), and pyrin.
[2][8] Notably, the PYD of the adaptor protein ASC has been demonstrated to function as a prion-like domain, forming a self-perpetuating polymer when activated.
In mice, the non-canonical inflammasome is activated by direct sensing of cytosolic bacterial lipopolysaccharide (LPS) by caspase-11, which subsequently induces pyroptotic cell death.
However, recent studies indicate high levels of inflammasome component expression in epithelial barrier tissues, where they have been demonstrated to serve as an important first line of defense.
[17][18] In 2002, it was first reported by Martinon et al.[17] that NLRP1 (NLR family PYD-containing 1) could assemble and oligomerize into a structure in vitro, which activated the caspase-1 cascade, thereby leading to the production of pro-inflammatory cytokines, including IL-1β and IL-18.
[19][20][21][18] Several PAMPs and DAMPs, including bacterial RNA and imidazoquinolines, viral DNA, muramyl dipeptide (MDP), asbestos, and silica, were found to induce an inflammasome response.
[18] These findings paved the way for present-day studies in the fields of innate immunity and cell death, where disease mechanisms and treatments are being investigated in relation to inflammasome assembly and activation.
Assembly of the inflammasome and the resulting inflammatory signaling cascade involve a well-orchestrated mechanism comprising upstream sensors, adapters, and downstream effectors.
The cleavage of GSDMD is also initiated by active caspase-1, which results in pyroptosis (where the cell releases its cytoplasmic content to induce pro-inflammatory signaling).
[36] NLRP1, NLRP3, and NLRC4 are members of the NLR family and are characterized by two common features: the first is a nucleotide-binding oligomerization domain (NOD), which can bind ribonucleotide-phosphates (rNTP) and plays an important role in self-oligomerization.
In addition to NOD and LRR, the NLRP1 structure consists of a PYD at its N-terminal, a FIIND motif, and a CARD at its C-terminus, which helps distinguish it from the other inflammasome sensors.
[45][46] NLRP3 oligomerization is activated by a large number of diverse stimuli, such as DAMPs, including crystalline matter (e.g., monosodium urate (MSU) crystals), alum, asbestos, calcium influx, mitochondrial reactive oxygen species (ROS), and extracellular ATP.
[2][47] The NLRP3 inflammasome is additionally known to assemble in response to PAMPs from pathogens, including viruses, such as influenza A,[48] bacteria, such as Neisseria gonorrhoeae,[30] bacterial toxins like nigericin and maitotoxin,[1] and fungi, such as Aspergillus fumigatus.
[61][62] Intracellular bacteria activate the inflammasome, resulting in the targeted expulsion of infected epithelial cells from the epithelium to reduce the bacterial load.
Furthermore, the NLRC4 inflammasome was found to reduce tumor load in a mouse model of colorectal carcinoma (CRC) by triggering the elimination of tumor-initiating cells.
The AIM2 inflammasome senses cytosolic dsDNA and plays a crucial role in host defense against DNA viruses and intracellular bacterial infections.
[63] As a result, pro-caspase-1 is recruited to the inflammasome complex, triggering a robust innate immune response and pyroptotic cell death.
[66][67][64] In addition, the AIM2 inflammasome also acts as an integral components of the AIM2-PANoptosome complex with pyrin and ZBP1 to promote PANoptosis and host defense in response to F. novicida and HSV1.
[70] Pyrin is an innate immune sensor that coordinates the assembly of the inflammasome in response to bacterial toxins as well as effector proteins via the detection of pathogen-driven alterations in cytoskeleton dynamics.
[72][73] The non-canonical inflammasomes are independent of caspase-1 and activate caspase-11 in mice, and caspase-4 and -5 in humans[2] upon sensing intracellular LPS, a prototypic PAMP that plays a significant role in sepsis and septic shock.
This initiates pyroptotic cell death by the cleavage of the pore-forming protein GSDMD[15] leading to the secondary activation of the canonical NLRP3 inflammasome and cytokine release.
[74][2][35][14] The primary function of the non-canonical inflammasome is to aid in the defense against Gram-negative bacteria,[11] as well as eliminate pathogens and alert neighboring cells by releasing alarmins, DAMPs, and canonical NLRP3 inflammasome-dependent cytokines.
[74] The non-canonical inflammasome plays key roles in endotoxemia and sepsis, making its components valuable targets for clinical intervention.
[74][76][77] Inflammasomes are crucial components of the innate immune system that initiate inflammatory responses and regulate host defenses by activating and releasing pro-inflammatory cytokines and inducing pyroptosis.
[82][83][84] The gain-of-function mutations in inflammasome components are also known to cause cryopyrin-associated periodic syndrome (CAPS), a group of congenital diseases characterized by IL-1β-mediated systemic inflammation.
Several agents, including anakinra, canakinumab, rilonacept, and IL-18–binding protein, have been developed to treat autoinflammatory diseases like CAPS and other conditions where inflammasomes can be hyperactivated.