Inflammasomes: Intracellular Regulators of Pathogen Recognition, Host Defense, & Inflammation

R&D Systems Tools for Cell Biology Research™ R&D Systems Tools for Cell Biology Research™ Inflammasomes: Intracellular Regulators of Pathogen Recognition, Host Defense, & Inflammation

P IL-1 & IL-18 Signaling Pathways Mechanisms to Reduce IL-1b or IL-18 Signaling IκB Inhibitors Mechanisms of Action IL-18 binding protein (IL-18 BP); Binds to IL-18 with higher affinity than either the cell bound or soluble IKK IL-18 BP forms of IL-18 R and prevents IL-18 signaling 2010 | Issue 3 · RnDSystems.com 2010 | Issue 3 · RnDSystems.com IL-1ra An IL-1 receptor antagonist that prevents IL-1 from binding to its receptor P IL-1 RII A decoy IL-1 receptor with a short cytoplasmic domain that is incapable of transducing an IL-1 signal IκB SIGIRR Single immunoglobulin IL-1-related receptor (SIGIRR); Prevents IL-1 RI/IL-1 RAcP heterodimerization IL-1β Signaling Soluble IL-1 RI or RII Soluble receptors that can bind to IL-1 and IL-1 RAcP, but are incapable of propagating a signal Inflammasome-mediated Caspase-1 Activation Regulates the Secretion of IL-1b & IL-18 NFκB . Lymphocyte activation TAB1/2 . Recruitment of in ammatory cells A soluble receptor that can bind to IL-1/IL-1 RI, but is incapable of propagating a signal; Enhances IL-1 Soluble IL-1 RAcP binding to soluble IL-1 RII Nod-like receptors (NLRs) are a subset of pattern recognition receptors (PRRs) found in the cytosol that are essential for detecting invading pathogens and initiating the innate immune response. TAK1 TRAF-6 . Induction of secondary cytokines, enzymes, in ammatory mediators, and acute phase proteins NLRs are activated either by bacterial, fungal, or viral molecules that contain pathogen-associated molecular patterns (PAMPs), or by nonmicrobial danger signals (DAMPs) released from damaged that regulate the local and systemic response cells. Upon activation, some NLRs oligomerize to form multiprotein inflammasome complexes that serve as platforms for the recruitment, cleavage, and activation of inflammatory caspases. IL-18 Rβ IL-1 RI Inflammasome oligomerization requires two signals, a priming signal that results in the transcription of Pro-IL-1b and Pro-IL-18 (➊-➋), and a second signal that promotes indirect JNK IL-18 IL-18 Signaling activation of the inflammasome, such as ion or membrane perturbations, reactive oxygen species (ROS), or ATP ➌( ). Inflammasome oligomerization leads to the activation of Caspase-1, followed TRAF-6 P IL-18 Rα b ➍ ➏ NADb FIND CARD IL-1β by the maturation and secretion NADof IL-1 FINDand IL-18CARD ( - ), and in some cases, an inflammatory form of cell death known as pyroptosis. Inflammasome/Caspase-1-dependent secretion of IL-1 P MyD88 IL-1 RAcP IL-18 BP ➐ MKK and IL-18 stimulates the inflammatory response by inducing the expression of secondary mediators that promote the recruitment of immune cells to the site of the infection ( ). In addition, IL-18 NFκB IRAK1/2 IRAK4 x AD NACHT x AD AP-1 IL-1 RAcP enhances the cytolytic activityNAD of naturalFIND killerCARD (NK) cells and promotes IFN-g production. To date, four inflammasome complexes (NLRP1, NLRP3, IPAF, and AIM2) have been partially characterized.NAD FIND NACHTCARD These complexes contain a specific NLR family protein or AIM2, the ASC and/or Cardinal adaptor proteins, and Pro-Caspase-1. BIR p38 x PYDAD NACHT x PYDAD BIRNACHT IL-1 Signaling Although the secretion of IL-1b and IL-18 are intended to combat infection, constitutive inflammasome activation and the subsequent overproduction of IL-1b or IL-18 can have detrimental effects IL-1ra IL-1 RI that are associated with autoinflammatory and autoimmune disorders. For these reasons, mechanisms that inhibit IL-1b and IL-18 signaling are of interest. Decoy or soluble receptors that sequesterNAD FIND CARD PYD BIRNAD FIND CARD BIR Inflammatory IL-1b, non-signaling IL-1b antagonists, and disruption of IL-1 receptor heterodimerization are intrinsic pathways that inhibit IL-1b signaling. Similarly, naturally occurring IL-18 bindingPYD protein Response IL-1 RAcP NAD NAD FIND CARD IL-1β (IL-18 BP) can prevent IL-18 fromx bindingAD toNACHT FINDits receptor.CARD Further research is necessary to characterize how inflammasome complexes are activated, the mechanisms by which IL-1b and IL-18x AD NACHT Inflammasomes: signaling can be regulated, and both the beneficial and detrimental effects associated with the inflammasome pathway. These findings may have therapeutic implications for inflammasome- Active IL-1β x AD NACHT x AD NACHT IL-18 Signaling IL-18 Rα IL-1β IL-1 RII related disorders, including autoinflammatoryPYD BIR disorders, Crohn’s disease, vitiligo, gout, asbestosis, and Alzheimer’s disease. . Induction of IFN-γ in T cells and NK cells Decoy Intracellular Regulators of PYD BIR . Induction of secondary pro-in ammatory PYD BIR cytokines, chemokines, cell adhesion molecules IL-18 SIGIRR Pathogen Recognition, PYD BIR . Induction of Fas Ligand, NO synthesis β NAD FIND CARD NAD FIND CARD IL-18 R DOMAIN ORGANIZATION OF THE NLR PROTEINS OLIGOMERIZED INFLAMMASOME COMPLEXES Active IL-18 IL-1 RI Host Defense, & Inflammation Human Name Mouse Name Family CARD-containing NLRs NLRP1 (NALP1) Inflammasome Select Microbial Activators x AD NACHT Pro-Caspase-1 Pro-Caspase-5 x NADAD FINDNACHTCARD Soluble NAD FIND CARD NLRP1/ASC/Pro-Caspase-1/Pro-Caspase-5 NAD FIND CARD Pattern recognition receptors (PRRs) expressed by CIITA (NLRA) CIIta (Nlra) NAD FIND CARDNLRA NAD FIND CARD IL-1 RI or RII NAD FIND CARD NAD FIND CARD x NAD BIR FIND CARD NAD FIND CARD macrophages, monocytes, dendritic cells, neutrophils, NOD1 (NLRC1) Nod1 (Nlrc1)PYDNADAD FINDNACHTCARDNLRC Pro-Caspase-5 Pro-Caspase-1 Pro-Caspase-1 Pro-Caspase-5 x ADBIR NACHT x AD NACHT ASC NLRP1 · Bacillus anthracis lethal toxin PYDx AD NACHT IL-1 RAcP x NADAD FINDNACHTCARD · Muramyl dipeptide (MDP) x NADAD FIND CARD and epithelial cells play a critical role in activation of NOD2 (NLRC2) Nod2 (Nlrc2)x AD NACHT NLRC x AD NACHT + Signal 2 ADBIR NACHT AD NACHT K DAMP/PAMP + IL-1 RI the innate immune response. Nod-like receptors (NLRs) PYD ASC NLRP1 Inflammasome Activation K Soluble IPAF (NLRC4) Ipaf (Nlrc4)PYDx BIR NLRC Pro-Caspase-5 Pro-Caspase-1 ASC NLRP1 PYD BIR PYD ADBIR NACHT Pro-Caspase-1 PYDx ADBIR NACHT ATP Bacterial Type III or IL-1 RAcP are cytoplasmic PRRs that detect intracellular microbial PYD BIR PYD BIR Human Name Mouse NamePYD BIR Family BIR-containing NLRs Pro-Caspase-1 Pro-Caspase-5 PYD BIR IV Secretion Systems Pro-Caspase-1 NLRP3 (NALP3) Inflammasome Select Microbial Activators PYD BIR components or endogenous danger signals. Following BIR ASC NLRP1 Pore-forming NAIP Naip1-7 PYD NLRB Pro-Caspase-1NLRP3/ASC/Cardinal/Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-5 PYD BIR Signal 1 Toxins Secretion of activation, some NLRs form inflammasome complexes Cardinal ASC NLRP3 · Adenovirus, Bacterial RNA Pannexin-1 Particulate Human Name Mouse Name Family PYD-containingPro-Caspase-5 NLRsPro-Caspase-1 ASC NLRP1 P2X7 Receptor IL-1β & IL-18 that induce the cleavage and activation of Caspase-1, CardinalPro-Caspase-1ASC NLRP3 · Candida albicans/Saccharomyces cerevisiae Activators + leading to the subsequent processing and secretion of NLRP1 (NALP1) Nlrp1a-c (Nalp1) NLRP Pro-Caspase-5 Pro-Caspase-1 ASC NLRP1 · Danger signals: ATP, NAD , b-amyloid ASC NLRP1 Cardinal ASC NLRP3 and particulates such as calcium pyrophosphate Endogenous Cytokine Active IL-1β IL-1b and IL-18. IL-1b and IL-18 induce the expression Nlrp2, Nlrp3 (Nalp3), Nlrp4a-g Pro-Caspase-1 Active IL-18 NLRP2-9 (NALP2-9), (Nalp4a-g), Nlrp5, Nlrp6, Cardinal ASC NLRP3 Pro-Caspase-1 dihydrate and monosodium urate PAMP NLRP Pro-Caspase-1ASC NLRP1 of secondary mediators that attract immune cells to NLRP11-14 (NALP11-14) Nlrp9a-c (Nalp9a-c), Nlrp12 Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-5 · Xenogenous compounds: Silica, asbestos, and alum Microbial Ligand (Nalp12), Nlrp14 (Nalp14) Pro-Caspase-1 · Influenza virus ROS the site of the infection. Although IL-1b and IL-18 have Pro-Caspase-1 IPAF IPAF · Listeria monocytogenes a beneficial role in promoting inflammation and NLRP10 (NALP10) Nlrp10 (Nalp10) NLRP Pro-Caspase-1Pro-Caspase-1 CardinalPro-Caspase-1ASC NLRP3Pro-Caspase-5 IL-1 RAcP Phagosome Pro-Caspase-5 Pro-Caspase-1 Pro-Caspase-1ASC NLRP1Pro-Caspase-5 · Lipopolysaccharide (LPS) Human Name Mouse Name FamilyCardinalUnknownASC N-terminalNLRP3 Domain Pro-Caspase-1 Pro-Caspase-5 · Muramyl dipeptide NAD(MDP) FIND CARD eliminating infectious pathogens, mutations that NAD FIND CARD Pro-Caspase-1 IPAF CardinalPro-Caspase-1Pro-Caspase-1ASC NLRPPro-Caspase-53 NAD FIND CARD ROS NLRC3NAD (NOD3), FINDNLRC5CARD IPAF Pro-Caspase-1IPAF IPAF Pro-Caspase-5 · Sendai virus TIR Domain result in constitutive inflammasome activation and the Nlrc3, Nlrc5 NLRC Cardinal ASC NLRP3 IL-1 RI (NOD27) ASC Pro-Caspase-5ASC NLRP1Pro-Caspase-1 ASC NLRP1 · Staphylococcus aureus Death Domain x AD NACHT Pro-Caspase-5 Pro-Caspase-1 Pro-Caspase-1Pro-Caspase-1ASC Pro-Caspase-1NLRPPro-Caspase-51 x overproduction of IL-1b and IL-18 have been linked x Pro-Caspase-1Pro-Caspase-5Pro-Caspase-1NAIP Pro-Caspase-1 x AD NACHT Phagolysosome NLRX1 (NOD9)AD NACHT Nlrx1 NLRX Pro-Caspase-5IPAF Pro-Caspase-1 Pro-Caspase-1ASC NAIPNLRP1 AD NACHT Pro-Caspase-5 Pro-Caspase-1 ASC IPAF NLRP1 to autoinflammatory and autoimmune disorders. Pro-Caspase-1 IPAF (NLRC4) InflammasomeASC Pro-Caspase-1NLRP1 Select Microbial Activators Toll-like Receptor MyD88 BIRDOMAIN ORGANIZATION OF RELATEDASC ADAPTORASC PROTEINSPro-Caspase-1NLRP1 TIRAP PYD Pro-Caspase-5ASC NLRP1Pro-Caspase-1 Pro-Caspase-1 Further research is necessary to identify factors that PYD BIR Pro-Caspase-1ASC IPAFNLRP1 IPAF/ASC/Pro-Caspase-1Pro-Caspase-1ASC IPAFNLRP1 PYD BIR ASC: Apoptosis-associated speck-like protein containing a CARD ASC NAIP IPAFNLRP1 Cardinal ASC NAIP NLRP3 PYD BIR MyD88 ASC NLRP1 Pro-Caspase-1 TRAM Membrane Perturbations regulate inflammasome activation, to characterize Pro-Caspase-1 IPAF Pro-Caspase-1Pro-Caspase-1 IPAF Cardinal Pro-Caspase-1Pro-Caspase-1ASC NLRPIPAF3 IPAF TRIF β Cardinal: CARD inhibitor of NFkB-activating ligands (found only in humans) Pro-Caspase-1ASC NLRP1 Pro-Caspase-1 IPAF · Pseudomonas aeruginosa Mature IL-1 2+ the cell type-specific effects of NLR-/inflammasome- Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-1 ASCPro-Caspase-1IPAF Cardinal ASC NLRP3 · Salmonella typhimurium Inflammasome Ca dependent signaling pathways, and to determine how Pro-Caspase-1 IPAF Cardinal ASCPro-Caspase-1NLRP3 NLRP3 In ammasome Cardinal ASC CardinalPro-Caspase-1ASCPro-Caspase-1NLRP3IPAF · Shigella flexneri Oligomerization Pro-Caspase-1ASC NLRPNAIP3 Cardinal ASC IPAF NLRP3 defects in these signaling pathways contribute to the DOMAIN KEY Cardinal ASCASCPro-Caspase-1NLRP3 Cardinal ASC NAIPNLRP3 Pyroptosis Mature IL-18 Cardinal ASC NLRP3 MKK Protein-Protein Interacting Domains Cardinal Pro-Caspase-1ASC NLRP3 development and progression of inflammation-related Cardinal ASC NLRPNAIP3 Cardinal ASC ASC ASC Pro-Caspase-1NLRPNAIP3 Caspase Recruitment Domain (CARD) Pro-Caspase-1Pro-Caspase-1IPAFIPAF Pro-Caspase-1IPAF pathological conditions. Cardinal ASC Pro-Caspase-1NLRP3 IPAF/NAIP/Pro-Caspase-1Pro-Caspase-1 Pyrin Domain (PYD) Pro-Caspase-1ASCAIM2 Pro-Caspase-1Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-1 Cytokine Processing Pro-Caspase-1Pro-Caspase-1 ASC Pro-Caspase-1IPAF IKK 2+ Pro-Caspase-1Pro-Caspase-1 IPAF Ca Baculovirus Inhibitor of Apoptosis Repeat DomainPro-Caspase-1 (BIR) IPAF Pro-Caspase-1 IPAF IPAF Pro-Caspase-1Pro-Caspase-1IPAFIPAF JNK ASC IPAFIPAF IPAF · Legionella pneumophila Unknown N-terminal Domain ASCAIM2 ASCPro-Caspase-1IPAF Pro-Caspase-1ASCAIM2 IPAFIPAF IPAF Pro-Caspase-1 Pro-Caspase-5 IPAF Pro-IL-18 Nucleotide-Binding/Oligomerization Domain Pro-Caspase-1 NAIPIPAFIPAF Pro-Caspase-1 Pro-Caspase-5 IPAF Pro-Caspase-1 Pro-Caspase-1 NAIPIPAF Pro-Caspase-1ASC IPAFIPAF Pro-Caspase-1 NAIP, CIITA, HET-E, TP-1 Domain (NACHT)ASCPro-Caspase-1 IPAFIPAF Pro-Caspase-1ASC IPAFIPAFIPAF Pro-IL-1β Pro-Caspase-1 IPAF ASCPro-Caspase-1AIM2 IPAFIPAF p38 Active Caspase-1 Pro-Caspase-5 Pro-Caspase-1 ASCPro-Caspase-1 IPAF Pro-Caspase-1 IPAF Proteasome Microbial Ligand Recognition Domain ASC NAIP ASC NLRPAIM21 Inflammasome IPAF Select Microbial Activators Pro-Caspase-5 Pro-Caspase-1 ASCPro-Caspase-1Pro-Caspase-1IPAF ASC NLRP1 ASC NAIP Leucine-Rich Repeat Domain (LRR) ASCPro-Caspase-1ASCAIM2 NAIP Pro-Caspase-1 P NAIPIPAF Pro-Caspase-1AIM2/ASC/Pro-Caspase-1NAIPIPAF NAIP Pro-Caspase-1 NAIP Hematopoietic Interferon-inducible Nuclear Protein with aNAIP 200 a.a. repeat (HIN200) NAIPIPAF ASC NLRP1 ASC ASCAIM2 Pro-Caspase-1NAIP P For additional copies of the BIObrief, please visit Other Domains ASC NLRP1 Pro-Caspase-1 IPAF Pro-Caspase-1 Pro-Caspase-1 NAIP Pro-Caspase-1 IκB IκB Pro-Caspase-1 IPAFIPAF ASCAIM2 NAIP · DS-DNA from virus, bacteria, or the host itself www.RnDSystems.com/go/BIObrief NACHT-Associated Domain (NAD) Pro-Caspase-1ASC IPAFIPAF Pro-Caspase-1 Pro-Caspase-1 Pro-Caspase-1 IPAF Pro-Caspase-1 IPAF AP-1 Function to Find Domain (FIIND) IPAF Pro-Caspase-1 IPAFIPAF NFκB Pro-Caspase-1 Pro-Caspase-1ASCAIM2 IPAFIPAF Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-1ASC IPAF NFκB Transcription of Activation Domain (AD) ASC CardinalIPAF ASC NLRP3 IPAF ASC Cardinal ASC NLRPOligomerized3 Pro-Caspase-1inflammasome complexes may consist of more subunits than what is shown. IL-1β and IL-18 Cardinal ASC NLRP3 ASC IPAF Cardinal ASC NLRP3 Pro-Caspase-1ASCASCAIM2 Pro-Caspase-1 CB111_issue3_OCT Pro-Caspase-1ASC ASC This illustration represents general processes suggested in the scientific literature and is not to be considered comprehensive nor definitive. Pro-Caspase-1 ASC Pro-Caspase-1ASC ASC Pro-in ammatory Cytokines Pro-Caspase-1 Pro-Caspase-1 ASC Pro-Caspase-1 ASCAIM2 Pro-Caspase-1 Pro-Caspase-1ASC Pro-Caspase-1 ASCAIM2 Pro-Caspase-1ASCAIM2 Pro-Caspase-1ASCAIM2 Pro-Caspase-1 ASCAIM2 Pro-Caspase-1ASC ASCAIM2 IPAF Pro-Caspase-1 IPAF IPAF ASCAIM2 IPAF ASCAIM2 Pro-Caspase-1ASCAIM2 ASCAIM2 Pro-Caspase-1 IPAF ASCAIM2 Pro-Caspase-1 Pro-Caspase-1 IPAF ASCAIM2 IPAF Pro-Caspase-1 IPAF ASC ASC ASCAIM2 NAIP NAIP NAIP NAIP

Pro-Caspase-1 IPAF Pro-Caspase-1 IPAF Pro-Caspase-1 IPAF Pro-Caspase-1 IPAF

ASC ASC Pro-Caspase-1 ASC Pro-Caspase-1 ASC ASCAIM2 Pro-Caspase-1 ASCAIM2 Pro-Caspase-1

ASCAIM2 ASCAIM2