Inflammasome activation occurs when the scaffold protein senses or binds its activating stimuli. However, many questions remain regarding inflammasome activation. We will now briefly discuss the mechanism of activation of the most well-characterized inflammasomes where major advances have been made.
Additionally, though NLRP1, which has many genetic variants in mice and rats, forms well-defined inflammasomes in these rodent models, activation of the single human NLRP1 paralog into an inflammasome is less well understood The NLRP3 inflammasome Figure 1 is activated in response to the widest array of stimuli, leading to the theory that the dissimilar agonists induce similar downstream events which are sensed by NLRP3 8 , 19 , The mechanisms of NLRP3 activation supported by the most studies include potassium efflux out of the cell, the generation of mitochondrial reactive oxygen species ROS , translocation of NLRP3 to the mitochondria, the release of mitochondrial DNA or cardiolipin, or the release of cathepsins into the cytosol after lysosomal destabilization 6 — 8 Figure 1.
Additionally, increases in intracellular calcium can activate the NLRP3 inflammasome 21 , 22 , but this is also not a requirement of all NLRP3 agonists Though many published studies support the involvement of lysosomal cathepsins, proteases that degrade internalized proteins, in NLRP3 inflammasome activation, it is important to note that this is not without some controversy However, recent findings have shown that priming rapidly licenses mouse NLRP3 inflammasome activation by inducing the deubiquitination of NLRP3 independent of new protein synthesis, while inhibition of deubiquitination inhibits human NLRP3 activation 26 , Current stimuli recognized as NLRP3 agonists that induce NLRP3 inflammasome formation include ATP, pore-forming toxins, crystalline substances, nucleic acids, hyaluronan, and fungal, bacterial, or viral pathogens 6 , 7.
These stimuli can be encountered during infection, either produced by pathogens or released by damaged host cells. Additionally, pathologic conditions in the body may promote formation of these stimuli in the absence of infection, such as the formation of inflammatory cholesterol crystals, as discussed in more detail later.
This causes ASC to convert to a prion-like form and generate long ASC filaments that are crucial to inflammasome activation. The close proximity of pro-caspase-1 proteins then induces auto-proteolytic maturation of pro-caspase-1 into active caspase Caspase-8 is a pro-apoptotic protease that initiates the external apoptosis pathway in response to external stimuli, such as FasL and TNF, and protects against an inflammatory form of cell death termed necroptosis It is now also recognized that caspase-8 is required for both the transcriptional priming and activation of the canonical and noncanonical NLRP3 inflammasomes in mice in response to pathogenic stimuli and ligands stimulating various different TLRs 32 — Additionally, caspase-8 was shown to bind and localize to ASC specks, further suggesting that caspase-8 is an important component of inflammasome complexes However, the exact molecular mechanism of how caspase-8 promotes caspase-1 activation has yet to be elucidated.
Notably, the exact role of caspasemediated inflammasome activation is somewhat controversial This raises the question of whether NLRC4 is a scaffolding protein and not a receptor 14 , T3SS is found in several gram negative bacteria and allows the bacteria to inject effector molecules into infected host cells.
By contrast to mice, only one human NAIP protein has been characterized, and it was found to bind only the T3SS needle protein 40 , suggesting a far more restrictive repertoire of ligands for the NLRC4 inflammasome in human cells than NLRP3, which responds to a plethora of stimuli.
In order for NLRC4 to be activated, its autoinhibition must be relieved to allow oligomerization with NAIP proteins, but how this occurs is unclear However, two new gain-of-function mutations have recently been identified in humans that cause severe spontaneous autoimmune syndrome, suggesting that the helical domain is responsible for this autoinhibition 44 , Though some reports indicate that mouse NLRC4 must be phosphorylated prior to inflammasome activation 46 , 47 , there are also conflicting reports indicating that phosphorylation is dispensable The autoinhibitory conformation of AIM2 is created by interactions of its two domains and relieved by the sugar phosphate backbone of dsDNA Interestingly, AIM2 does not appear to recognize a specific sequence or structure of dsDNA but instead requires a dsDNA strand of at least 80 base pairs for optimal inflammasome activation Recently, a noncanonical AIM2 inflammasome was shown to mediate protection against Francisella novicida IRF1 increases the expression of guanylate binding proteins, which increase the intracellular killing of the bacterium.
A developing area of interest in the inflammasome field is the noncanonical inflammasome formed by caspase in mice Figure 2C. Caspase was initially found to be important for the activation of caspase-1 and caspase-3 Though humans do not express caspase, recent studies indicate that caspase-4 and caspase-5 in human cells serve a similar function 56 , 57 Figure 2C. As caspasedeficient mice are protected from endotoxic shock 53 , further study of the noncanonical inflammasome in human cells is of great interest.
ASC has long been recognized to redistribute upon inflammasome activation from the nucleus to the cytosol and form a large perinuclear aggregate in cells 58 , Importantly, as activation of all major inflammasomes is associated with speck formation 59 , this suggests that inflammasome activation propagates inflammation from cell to cell.
The buildup of specks at sites of inflammation has serious implications for inflammatory diseases, as injection of purified ASC specks into mice in vivo was shown to propagate inflammation The kinases Syk and JNK, which activate in response to a vast array of stimuli and lead to the phosphorylation of many downstream targets, mediate phosphorylation of ASC upon NLRP3 inflammasome activation, and inhibition of these kinases prevented ASC speck formation and blocked caspase-1 activation This suggests that phosphorylation of ASC may be necessary for ASC to switch to its prion form and form self-propagating filaments.
This also suggests that kinase inhibition may have potential therapeutic use against inflammatory diseases in the absence of more targeted inhibitors. Here we focus on neurologic disorders and metabolic diseases, both of which are not traditionally considered to be inflammatory diseases, but are increasingly recognized as having an inflammatory component that contributes significantly to the disease process. Misfolded protein aggregates and aberrant accumulation of certain metabolites accompanied with those diseases are endogenous DAMPs that have been proved to be direct activators of the NLRP3 inflammasome, which plays a critical role in the initiation and progress of those diseases.
Demyelination partially disrupts the communication of the nervous system, resulting in physical, mental, and psychiatric challenges, among other issues. Presently, MS has no cure and shortens the lifespan of patients approximately 5 to 10 years Recently, Nlrp3 expression has been shown to increase in the spinal cord during EAE progression and Nlrp3 -deficient mice showed a dramatically delayed course and reduced severity of disease, accompanied by fewer infiltrating inflammatory cells and reduced astrogliosis 64 , In addition, a study using a cuprizone model of MS also showed that Nlrp3 -deficient mice had delayed demyelination and oligodendrocyte loss Expression of Nlrp3 in antigen-presenting cells APCs was required to stimulate T helper type 1 Th1 and Th17 cells to respond to brain autoantigen in one study In agreement with this, Asc -deficient mice were even more resistant to EAE than Casp1 -deficient mice This leads to disruption of the phagolysosome and activation of the NLRP3 inflammasome due to cathepsin B release.
This activation of caspase-1 required phagocytosis, cathespin B, and ROS. However, this study did not use the more relevant microglial cells and astrocytes, and the involvement of NLRP3 was not directly proven by an in vivo animal model. In a PD model mouse in which PD is induced by loss of nigral dopaminergic neurons caused by treatment with neurotoxin 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP , mice lacking Nlrp3 are resistant to developing PD.
Interestingly, dopamine was found to negatively regulate NLRP3 activation in both primary microglia and astrocytes via a dopamine D1 receptor DRD1 -cyclic adenosine monophosphate cAMP signaling pathway These studies suggest that dopamine-producing neurons and the NLRP3 inflammasome regulate each other in a bidirectional fashion, where the inflammasome can damage these neurons, while dopamine from these neurons can inhibit NLRP3 function.
Chronic inflammation plays an essential role in the initiation and progression of metabolic disorders such as type 2 diabetes T2D , obesity, gouty arthritis, and atherosclerosis Cholesterol crystals and white blood cells accumulate on the arterial wall, limiting the flow of oxygen-rich blood to the organs It is commonly referred to as a hardening or furring of the arteries, which can lead to life-threatening complications such as heart attack and stroke.
It has long been suggested, on the basis of evidence from mouse models 88 — 90 , that IL, a product of inflammasome activation, may have crucial roles in the initiation and progression of atherosclerosis.
Furthermore, human atherosclerotic plaques have elevated concentrations of IL and IL receptors compared to disease-free arterial tissues. Apolipoprotein E ApoE is important for proper cholesterol metabolism. In ApoE-deficient mice, which spontaneously develop atherosclerotic lesions, elevated IL levels have been shown to cause vascular inflammation and enhance the instability of atherosclerotic plaques, while ILdeficiency resulted in reduced atherosclerotic lesion size 89 , 91 , These cholesterol crystals formed intracellularly activate the NLRP3 inflammasome in vitro in both mouse and human cells through phagolysosomal damage, a mechanism dependent on both cathepsin B and cathepsin L 88 Figure 4A.
In vivo , intraperitoneal injection of cholesterol crystals in mice induced acute inflammation that was attenuated by the deficiency of NLRP3 inflammasome components, cathepsin B, and cathepsin L.
CD36 also facilitates the internalization of oxLDL and its intracellular conversion to cholesterol crystals, which disrupt the phagolysosome and activate the NLRP3 inflammasome through cathepsin release. Phagocytosis of extracellular cholesterol crystals may also contribute to inflammasome activation. Cathepsin inhibition prevents the NLRP3 inflammasome activation induced by cholesterol crystals.
CD36 facilitates the internalization of soluble islet amyloid polypeptide IAPP , which is converted intracellularly to its amyloid form. This disrupts the phagolysosome and activates the NLRP3 inflammasome due to cathepsin release.
Mice lacking the LDL receptor are prone to developing atherosclerotic plaques. When these mice are fed a high-cholesterol diet, they have markedly reduced lesion size if the bone marrow cells lack Nlrp3 , Asc , or Il1a and Il1b Type 2 diabetes T2D is a major global health threat resulting in insulin resistance and is a chronic inflammatory disease characterized by elevated circulating levels of TNF, interleukins, and cytokine-like proteins known as adipokines released from adipose tissue Elevation of NLRP3 inflammasome activity in myeloid cells from T2D patients when compared with those from unaffected individuals has been described This is accompanied by reduced inflammatory cytokine levels in the serum and metabolic tissues such as liver and adipose tissue in conjunction with increased insulin-PI3K-Akt signaling 99 , — These studies provide a direct link between the NLRP3 inflammasome, chronic inflammation, and insulin resistance.
Finally saturated fatty acids such as palmitate and ceramide that arise from a high fat diet and induce type 2 diabetes can induce NLRP3 inflammasome activation 99 , Figure 4B. Using the human THP-1 cell line, others have shown that unsaturated fatty acid can prevent NLRP3 activation, presenting another way to reduce inflammation Obesity is characterized by excessive expansion of adipose tissue due to adipocyte hypertrophy and immune cell infiltration Obesity-associated inflammation leads to functional abnormality of adipocytes, resulting in elevated circulating levels of FFAs and ectopic lipid accumulation This can subsequently give rise to multiple metabolic disorders such as atherosclerosis and T2D, as discussed previously.
In this section, we will focus on discussing the involvement of inflammasome components in the development of obesity and adipose inflammation. Caspase-1 expression was found in both human and mouse adipose tissues and increases with adipocyte differentiation and obesity development Differentiated adipocytes with caspase-1 deficiency also have improved adipogenesis and insulin sensitivity compared to wild-type control cells. To establish the direct link between inflammasome activity and obesity development, HFD- or genetically-induced obese animals lacking inflammasome components have been studied , It was initially reported that caspase-1 contributes to adipose tissue formation, as mice lacking Casp1 have reduced adipocyte size, reduced fat mass, increased adipogenic gene expression and improved insulin sensitivity.
Furthermore in the HFD-induced obesity model, mice lacking Casp1 gained less weight than wild-type controls did. Interestingly, caspase-1 blockade resulted in decreased lipogenesis and higher fat oxidation than in control mice but did not affect food intake, suggesting the potential mechanism by which caspase-1 promotes obesity However, a recent study reported contradictory results that mice lacking Casp1 were more obese than control mice including having increased fat mass compared with controls The difference may be due to the variation in intestinal microbiota in mice raised in different animal facilities, as intestinal microbiota has been demonstrated to play a significant role in metabolic diseases Additionally, IL, one of the products of inflammasome activation, has been shown to protect mice from obesity as mice lacking Il18 developed obesity due to increased food intake This provides another possibility for the discrepancy in obesity phenotypes observed in Casp1- deficient mice.
As regards the role of caspase-1 in obesity, studies have shown that it is likely that caspase-1 contributes to obesity through various mechanisms. It was previously thought that macrophages accumulate within inflamed adipose tissue to produce caspase-1 However, recent studies in mice have shown that a major source of caspase-1 in adipose tissue is independent of infiltrating macrophages Furthermore, sirtuin 1 SIRT1 , a deacetylase which can regulate metabolism and protect from obesity, was recently shown to be a caspase-1 substrate.
Adipocyte-specific Sirt1 knockout resulted in spontaneous obesity, and SIRT1 protein was cleaved and inactivated in adipose tissues by active caspase-1 under the HFD stress However, the mechanism of inflammasome and caspase-1 activation in adipocytes needs clarification. A strong association between obesity and leukocytosis exists, and inflamed adipose tissue from obese mice was recently found to induce monocytosis in recipient wild type mice Inappropriate inflammasome activity has been incriminated in the pathogenesis of neurodegenerative disease and metabolic disorders.
Therefore, inhibitors of the inflammasomes could offer greater therapeutic promise for this condition. Importantly, glyburide has been shown to efficiently prevent endotoxic-shock-induced lethality in the animal model of this disease A recently identified group of NLRP3 inhibitors targeting P2X7 signaling is the nucleoside reverse transcriptase inhibitors NRTIs , which are mainly used to block retrovirus replication.
NRTIs have efficacy on several inflammatory and autoimmune diseases in mouse models Cofactors for inflammasome activation Some inflammasome sensor molecules require co-receptors to recognize their ligands or to be stabilized in their activated states. Box 1 Sensing of mitochondrial stress. Open in a separate window. Figure 1. Cell-extrinsic inflammasome regulation Cell-autonomous regulatory feedback loops, as well as complex networks of direct cell—cell signals and indirect signals via messenger substances, regulate cellular activation.
Figure 2. Negative regulation of inflammasome activation An inflammatory response should subside once it has carried out its function. Cell-intrinsic inflammasome regulation When the function of a cell is compromised or the survival of the cell poses a danger to the whole organism, it should be eliminated.
Box 2 Oligomerization of death-inducing molecular platforms. Figure 3. Regulation by interacting host proteins In addition to general cellular conditions such as ion concentrations and the nutritional state, specific regulatory proteins have evolved that regulate inflammasome formation TABLE 1.
Table 1 Regulatory proteins of the inflammasomes. Conclusion and future perspectives In this Review, we summarize our rapidly evolving understanding of how inflammasomes are activated and we highlight the many mechanisms that are involved in their regulation. Box 3 Pharmacological interference of inflammasome activation. Acknowledgements The authors would like to thank C.
Glossary ASC An adaptor protein that was originally found to form protein precipitates in apoptotic cells that are termed protein specks Pyroptosis A rapid form of cell death following caspase 1 activation which shares characteristics with both apoptosis such as DNA fragmentation and necrosis such as cell swelling and rupture Apoptosome A large multimeric protein complex of apoptotic protease-activating factor 1 APAF1 that recognizes cytochrome c release from damaged mitochondria and activates caspase 9 Death-fold domains Commonly found in proteins that are involved in cell death pathways and in inflammasomes.
The four main death-fold domains — the pyrin domain caspase activation and recruitment domain CARD , death domain and death effector domain — associate with each other through homotypic interactions NOD-like receptor NLR. A protein that contains amino-terminal pyrin caspase-recruitment domains or other signalling domains, followed by a NACHT domain and carboxy-terminal leucine-rich repeats. Some NLR proteins are involved in forming inflammasomes. Two other non-canonical inflammasomes have also been described so far: one containing dectin 1, MALT1 mucosa-associated lymphoid tissue lymphoma translocation protein 1 , ASC and caspase 8 termed the non-canonical caspase 8 inflammasome , and a caspase activating platform that has not yet been fully described Ripoptosome A cytosolic multiprotein complex that induces cell death following genotoxic stress or depletion of inhibitor of apoptosis protein IAP.
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Latz E 1. Affiliations 1 author 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract In response to injurious or infectious agents caspase-1 activating multiprotein complexes, termed inflammasomes, assemble in the cytoplasm of cells. Activated caspase-1 cleaves the proforms of the interleukin-1 cytokine family members leading to their activation and secretion. The IL-1 family cytokines have multiple proinflammatory activities implicating them in the pathogenesis of many inflammatory diseases.
Numerous different molecular entities, such as various crystals, pore-forming toxins, or extracellular ATP can trigger the NLRP3 inflammasome. Free full text. Curr Opin Immunol. Author manuscript; available in PMC Feb 1. PMID: Eicke Latz. Author information Copyright and License information Disclaimer.
Eicke Latz: ude. Copyright notice. The publisher's final edited version of this article is available at Curr Opin Immunol. See other articles in PMC that cite the published article. Go to:. Open in a separate window. Figure 1. Figure 2. Toll-like receptors. Annu Rev Immunol. The inflammasomes: guardians of the body. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. The NLR gene family: a standard nomenclature. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
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Franklin, B.
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