PubMed: 23702978

Title
Activation and regulation of the inflammasomes.
Journal
Nature reviews. Immunology
Volume
13
Issue
None
Pages
397-411
Date
2013-06-01
Authors
Xiao TS | Latz E | Stutz A

Evidence 814fda10b5

RIG-I is widely known as a PRR that senses RNA and that signals via mitochondrial antiviral signalling protein (MAVS) to induce an interferon (IFN) response2, and IFI16 has been suggested to be a DNA sensor that signals via the protein STING (stimulator of IFN genes; also known as TMEM173) to generate an IFN response23.

Evidence 40a81d6a00

One checkpoint is that bacterial mRNA from live bacteria (also known as vita-PAMPs)44 activates NLRP3; the other checkpoint is that TLR4- and TRIF (TIR domain-containing adaptor protein inducing IFNβ)-dependent signalling — which is triggered by bacterial lipopolysaccharide (LPS) — mediate the secretion of type I IFNs, inducing pro-caspase 11 expression and activation by triggering the IFNα/β receptor (IFNAR) (FIG. 1).

Evidence 8fead530a9

A few molecules, such as amyloid-β, can induce both NLRP3 priming through TLR activation and NLRP3 inflammasome activation68.

Evidence d8cdbc5378

The mobilized Ca2+ has many molecular targets, including TGFβ-activated kinase 1 (TAK1; also known as MAP3K7) (REF. 86).

Evidence 0348d300d1

This channel senses intracellular ROS and responds by opening itself to facilitate Ca2+ influx into the cell; this is intriguing considering that both ion fluxes and the oxidative state (see below) have important roles in NLRP3 inflammasome activation.

Evidence f22416eda7

NLRP1 recognizes muramyl dipeptide, which is a bacterial peptidoglycan

Evidence 6054b77776

In addition, T cell-derived IFNγ has been shown to downregulate the activity of NLRP3 via activation of inducible nitric oxide synthase (iNOS) in a mouse model of tuberculosis71; nitric oxide (NO) induces NLRP3 nitrosylation and thereby inhibits NLRP3 activity.

Evidence d43ef1780a

Indeed, the binding of cytochrome c that has been released from mitochondria to apoptotic protease-activating factor 1 (APAF1) and the subsequent assembly of the apoptosome only occurs when subphysiological K+ concentrations are reached in compromised cells77,78.

Evidence 1aa1ef910a

Similarly, activation of the NLRP1B and NLRP3 inflammasomes depends on low K+ concentrations in intracellular compartments79, and a low K+ concentration promotes the assembly of the ASC speck6.

Evidence 63774838a4

In addition, high extracellular levels of K+ can block IL-1β release after NLRC4 and AIM2 inflammasome formation80,81, which indicates that low intracellular K+ levels might also be required for the activation of these inflammasomes.

Evidence bd2ec5cf0f

In particular, ROS facilitate the assembly of the apoptosome in several ways.

Evidence 4f3863b75c

In the presence of the translation inhibitor cycloheximide, TRIF signalling that is downstream of TLR3 or TLR4 leads to pro-IL-1β processing by caspase 8 (REF. 55).

Evidence 6374fbe840

In addition, type I IFNs can reduce IL-1β and IL-18 release by functioning at two levels.

Evidence 3438fbff3c

IFNs upregulate AIM2 expression but they downregulate IL-1β expression and inhibit the NLRP3 inflammasome.

Evidence d45cb486cd

Thus, it is not surprising that effector and memory CD4+ T cells have the capacity to inhibit the activation of the NLRP1 and NLRP3 inflammasomes in a contact-dependent manner, possibly via TNFR superfamily molecules such as CD40 ligand (CD40L)70.

Evidence 8ad24d2dfd

The transcription of pro-IL-1β is induced by the activation of the transcription factor nuclear factor-κB (NF-κB), whereas pro-IL-18 is constitutively expressed and its expression is increased after cellular activation.

Evidence fe22bf6c86

Furthermore, in response to genotoxic stress, the ripoptosome assembles and activates caspase 8.

Evidence 491eae70a6

The authors proposed that another, not yet characterized, ER stress pathway activates the NLRP3 inflammasome90.

Evidence 4d5c5e2b3b

Furthermore, autophagy can regulate both apoptosis and inflammasome assembly, and, depending on the conditions, can be either pro- or anti-apoptotic104

Evidence 04b2fe20d7

For inflammasome activation and IL-1β release, autophagy is a negative regulator:

Evidence 0edd18a10e

NLRC4 and NLRP1 can both activate caspase 1 through their CARDs without recruiting ASC; however, the recruitment of ASC greatly enhances the formation of the complex and the processing of IL-1β7,13–16.

Evidence 86f7924c79

In the original description of the inflammasome, human NLRP1 was shown to recruit and to activate an additional inflammatory caspase, namely caspase 5, via its CARD3.

Evidence dbf3f2e47f

Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18.

Evidence 6d6508a0f2

Once the protein complexes have formed, the inflammasomes activate caspase 1, which proteolytically activates the pro-inflammatory cytokines interleukin-1β (IL-1β)3 and IL-18.

Evidence 1b9bfce108

Indeed, inflammasomes (which induce pyroptosis through caspase 1 or caspase 11 activation) and apoptosomes (which activate caspase 9 in response to cytochrome c release from mitochondria) are two mechanisms by which compromised cells are eliminated.

Evidence eab9a89287

In addition, inflammasome activation causes a rapid, proinflammatory form of cell death called pyroptosis4.

Evidence b580da5b84

The formation of this complex activates RIP3, which is necessary for the cleavage of pro-IL-1β by both the NLRP3-caspase 1 and the caspase 8 pathways56 (FIG. 1).

Evidence 7b2bdc8e67

NLRP1 has been shown to bind directly to its ligand muramyl dipeptide in vitro and this was demonstrated to be sufficient to activate the assembly of an inflammasome.

Evidence 49ad3e47e3

Using its CARD, ASC brings monomers of procaspase 1 into close proximity, which initiates caspase 1 self- cleavage and the formation of the active heterotetrameric caspase 1.

Evidence bd519f3603

CARD8 has multiple functions in regulating apoptosis, one of which is to directly bind to procaspase 9 and to suppress its activation109.

Evidence ee8c6a36d0

Active caspase 1 proteolytically activates a number of proteins8, including pro-IL-1β and pro-IL-18 (REFS 9,10), and induces their release via a non-classical secretion pathway11.

Evidence d67555c42e

Caspase 1mediated activation of members of the IL-1β cytokine family leads to the recruitment and the activation of other immune cells, such as neutrophils, at the site of infection and/or tissue damage.

Evidence 2ceaafd380

Similarly, mouse caspase 12, which is a paralogue of caspase 1, interacts with caspase 1 to reduce its activity110

Evidence b64272fc00

For example, following sensing of fungal components by the PRR dectin 1 that is expressed on human dendritic cells, signalling via the kinase SYK leads to the formation of a complex that is composed of caspase 8 and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1); this complex binds to ASC, which possibly recruits cleavage substrates53. The MALT1-ASC-caspase 8 complex directly mediates IL-1β maturation53.

Evidence 22f30dddb4

One additional factor that can mediate IL-1β processing and activation is caspase 8 (FIG. 1)

Evidence 6253133985

In addition, it was recently shown that CD95 signalling mediates IL-1β and IL-18 processing through the activation of caspase 8 (REF. 60) (FIG. 1).

Evidence 9c15c5c47b

Pyroptosis in response to live Gram-negative bacteria but not in response to other inflammasome triggers is entirely dependent on caspase 11, whereas caspase 1 is dispensable for this process41

Evidence 091df25602

However, a requirement for the interaction of NLRP1 with nucleotide-binding oligomerization domain-containing protein 2 (NOD2), which is another receptor for muramyl dipeptide, has been described.

Evidence 6682d5cee8

Finally, heat shock proteins (HSPs) also have important roles in the regulation of cell death, and it has been shown that HSP90 and the cochaperone ubiquitin ligase-associated protein SGT1 are required for NLRP3 activation (REF. 129).

Evidence d0b3c79560

It is known that about 60% of patients with cryopyrin-associated periodic syndrome (CAPS) carry activating mutations in the coding sequence of NLRP3 itself or in other inflammasome components69.

Evidence fc8aefdfcb

Furthermore, the amount of NLRP3 mRNA is tightly regulated by the microRNA miR-223, which leads to decreased NLRP3 protein levels and, thus, influences the threshold of NLRP3 activation74,75.

Evidence d29340b167

In addition, AIM2 expression can be induced by IFNβ and IFNγ65,66.

Evidence 32b51ab8ac

First, a bacterial Toll-like receptor (TLR) activator leads to cellular priming and upregulation of NLRP3 and pro-IL-1β expression (the priming checkpoint in the standard model)37,38.

Evidence 184c74e2a9

Many innate immune signalling or cytokine receptors, such as the TNFR, activate transcription of NLRP3 and thereby influence the susceptibility of immune cells to NLRP3 inflammasome triggers37,38 (FIG. 2).

Evidence c759585c21

The ripoptosome contains caspase 8, FAS-associated death domain protein (FADD) and receptor-interacting protein 1 (RIP1; also known as RIPK1), and forms spontaneously in response to loss or inhibition of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP), inhibitor of apoptosis protein 1 (IAP1; also known as BIRC3) and IAP2 (also known as BIRC2) (REF 56).

Evidence 515978f7f1

NLRP3 deubiquitylation is mediated by the K63-specific deubiquitinase BRCC3 (REF. 63).

Evidence 4e78399aca

CARD-only proteins (COPs) can also inhibit caspase 1 activation112. CARD18 (also known as ICEBERG) and CARD16 (also known as pseudoICE and COP1) were the first ‘decoy’ COPs to be described113.

Evidence 5d9ee75b22

CARD17 (also known as INCA), which is another decoy protein, is upregulated by IFNγ to suppress IL-1β generation114.

Evidence 8168e54883

By contrast, nitrosylation of caspase 9 inhibits its function94. Similarly, caspase 1 can be inhibited by nitrosylation95, which suggests that modification by reactive molecules is a general mechanism for the regulation of caspase activity.

Evidence 0a0e27a22a

Another regulator of Ca2+, namely C/EPB-homologous protein (CHOP; also known as DDIT3), has been implicated in NLRP3 inflammasome activation89

Evidence 5982584a7b

Protein synthesis could be inhibited by the phosphorylation of the initiation factor eukaryotic translation initiation factor 2 subunit-α (EIF2α; also known as EIF2S1).

Evidence 425f5998ef

Indeed, activation of the TNFR family member CD95 (also known as FAS) can induce IL-1β processing that is independent of inflammasomes and of caspase 1 (REF. 59).

Evidence c35346fd67

Even if the expression of pro-caspase 11 could be induced independently of IFN signalling, caspase 11 activation in macrophages in response to Salmonella enterica subsp. enterica serovar Typhimurium infection is dependent on IFNAR1 as well as signal tranducer and activator of transcription 1 (STAT1)46.

Evidence 0693b6d86a

In addition, IL-1α, which also activates IL-1R, could contribute to the inflammatory response in vivo.

Evidence bf676049ff

In mice, NAIP (NLR family, apoptosis inhibitory protein) family proteins sense the proteinaceous NLRC4 activators and, in turn, activate the assembly of the NLRC4 inflammasome.

Evidence 74d7382a19

In the context of NLRC4 activation, caspase 11 was shown to interact with cofilin.

Evidence b73dbd5f92

Indeed, NLRP12 can function as a positive regulator of dendritic cell migration or as a negative regulator of non-canonical NFκB signalling20,21, and NLRP6 can negatively regulate innate immunity22.

Evidence a6a0a8739a

NLRC4 can only be activated by S . Typhimurium after a specific serine residue has been phosphorylated by protein kinase Cδ (PKCδ; encoded by PRKCD ), which depends on the recognition of both flagellin and the type III secretion system.

Evidence 666d726b0d

Indeed, a number of non-caspase proteases such as proteinase 3 have the ability to activate IL-1β in an inflammasome-independent manner11.

Evidence 9a1d383acf

POP1 (also known as PYDC1 and ASC2) and POP2 (also known as PYDC2) inhibit the interactions between the inflammasome sensor molecules and ASC115–117.

Evidence 225de51513

Another transient receptor potential channel — TRPM2 — has also been implicated in NLRP3 activation in response to crystalline substances88.

Evidence eea0c390a1

One study found that Mefv deletion in mice lead to increased IL-1β release without influencing caspase 1 activity or inflammasome assembly.

Evidence e42b4e52f5

At the same time, we have learnt that immune dysregulation contributes to prevalent diseases in Western societies such as atherosclerosis, type 2 diabetes, cancer and neurodegenerative diseases.

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.