Infl ammasomes: Intracellular Regulators of Pathogen Recognition, Host Defense, and Infl ammation Mechanisms to Reduce IL-1β or IL-18 Signaling P IL-1 & IL-18 Signaling Pathways Infl ammasome-mediated Caspase-1 Activation Regulates the Secretion of IL-1β & IL-18 IκB Inhibitors Mechanisms of Action 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. IL-18 BP IL-18 binding protein (IL-18 BP); Binds to IL-18 with higher a nity than either the cell bound or soluble 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 IKK forms of IL-18 R and prevents IL-18 signaling IL-1ra An IL-1 receptor antagonist that prevents IL-1 from binding to its receptor cells. Upon activation, some NLRs oligomerize to form multiprotein in ammasome complexes that serve as platforms for the recruitment, cleavage, and activation of in ammatory caspases. P IL-1 RII A decoy IL-1 receptor with a short cytoplasmic domain that is incapable of transducing an IL-1 signal In ammasome oligomerization requires two signals, a priming signal that results in the transcription of Pro-IL-1β and Pro-IL-18 (-), and a second signal that promotes indirect IκB IL-1β Signaling SIGIRR Single immunoglobulin IL-1-related receptor (SIGIRR); Prevents IL-1 RI/IL-1 RAcP heterodimerization activation of the in ammasome, such as ion or membrane perturbations, reactive oxygen species (ROS), or ATP (). In ammasome oligomerization leads to the activation of Caspase-1, followed NFκB . Lymphocyte activation 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 TAB1/2 by the maturation and secretion of IL-1β and IL-18 (-), and in some cases, an in ammatory form of cell death known as pyroptosis. In ammasome/Caspase-1-dependent secretion of IL-1NADβ FIND CARD . 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 NAD FIND CARD TAK1 TRAF-6 . Induction of secondary cytokines, enzymes, Soluble IL-1 RAcP binding to soluble IL-1 RII and IL-18 stimulates the in ammatory 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 in ammatory mediators, and acute phase proteins that regulate the local and systemic response enhances the cytolytic activity ofx naturalAD killerNACHT (NK) cells and promotes IFN-γ production. To date, four in ammasome complexes (NLRP1, NLRP3, IPAF, and AIM2) have been partially characterized.NADx ADFIND NACHTCARD IL-18 Rβ NAD FIND CARD IL-1 RI These complexes contain a speci c NLR family protein or AIM2, the ASC and/or Cardinal adaptor proteins, and Pro-Caspase-1. JNK IL-18 IL-18 Signaling x PYD BIR AD NACHT x PYDAD BIRNACHT TRAF-6 Although the secretion of IL-1β and IL-18 are intended to combat infection, constitutive in ammasome activation and the subsequent overproduction of IL-1β or IL-18 can have detrimental e ects P IL-1β IL-18 Rα P MyD88 IL-1 RAcP that are associated with autoin ammatory and autoimmune disorders. For these reasons, mechanisms that inhibit IL-1β and IL-18 signaling are of interest. Decoy or soluble receptors that sequesterNAD FIND CARD MKK IL-18 BP PYD BIRNAD FIND CARD κ IRAK1/2 IRAK4 IL-1β, non-signaling IL-1β antagonists, and disruption of IL-1 receptor heterodimerization are intrinsic pathways that inhibit IL-1β signaling. Similarly, naturally occurring IL-18 bindingPYD proteinBIR NF B AP-1 IL-1 RAcP NAD x NAD FIND CARD x FIND CARD (IL-18 BP) can prevent IL-18 from bindingAD toNACHT its receptor. Further research is necessary to characterize how in ammasome complexes are activated, the mechanisms by which IL-1β and IL-18 AD NACHT p38 signaling can be regulated, and both the bene cial and detrimental e ects associated with the in ammasome pathway. These ndings may have therapeutic implications for in ammasome- IL-1 RI IL-1 Signaling x AD NACHT x AD NACHT IL-1ra related disorders, including autoin PYD ammatoryBIR disorders, Crohn’s disease, vitiligo, gout, asbestosis, and Alzheimer’s disease. PYD BIR Inflammatory PYD BIR Response IL-1β IL-1 RAcP NADPYD BIR DOMAIN ORGANIZATIONNAD FIND CARD OF THE NLR PROTEINS OLIGOMERIZED INFLAMMASOME COMPLEXES FIND CARD IL-18 Signaling Active IL-1β IL-1 RII Human Name Mouse Name Family CARD-containing NLRs NLRP1 (NALP1) Infl ammasome Select Microbial Activators IL-18 Rα IL-1β x AD NACHT Pro-Caspase-1 Pro-Caspase-5 x NADAD FINDNACHTCARD . Induction of IFN-γ in T cells and NK cells Decoy CIITA (NLRA) CIIta (Nlra) NAD FIND CARDNLRA NLRP1/ASC/Pro-Caspase-1/Pro-Caspase-5 NAD FIND CARD . Induction of secondary pro-in ammatory NAD FIND CARD NAD FIND CARD cytokines, chemokines, cell adhesion molecules IL-18 SIGIRR NAD FIND CARD NAD FIND CARD x NAD BIR FIND CARD NAD FIND CARD . Induction of Fas Ligand, NO synthesis IL-18 Rβ 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 Active IL-18 IL-1 RI x NADAD FINDNACHTCARD Muramyl dipeptide (MDP) x NAD FIND CARD NOD2 (NLRC2) Nod2 (Nlrc2)x AD NACHT NLRC x AD NACHT Soluble ADBIR NACHT x AD NACHT PYD ASC NLRP1 IPAF (NLRC4) Ipaf (Nlrc4)PYDx BIR NLRC Pro-Caspase-5 Pro-Caspase-1 ASC NLRP1 PYD BIR IL-1 RI or RII PYD ADBIR NACHT Pro-Caspase-1 PYDx ADBIR NACHT PYD BIR PYD BIR Human Name Mouse NamePYD BIR Family BIR-containing NLRs Pro-Caspase-1 Pro-Caspase-5 PYD BIR IL-1 RAcP Pro-Caspase-1 NLRP3 (NALP3) Infl ammasome Select Microbial Activators PYD BIR Signal 2 PYD BIR ASC NLRP1 K+ DAMP/PAMP IL-1 RI NAIP Naip1-7 NLRB Pro-Caspase-1NLRP3/ASC/Cardinal/Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-5 PYD BIR Inflammasome Activation K+ Soluble Cardinal ASC NLRP3 Bacterial Type III or Human Name Mouse Name Family PYD-containingPro-Caspase-5 NLRsPro-Caspase-1 ASC NLRP1 Adenovirus, Bacterial RNA ATP IL-1 RAcP CardinalPro-Caspase-1ASC NLRP3 Candida albicans/Saccharomyces cerevisiae IV Secretion Systems + Pore-forming NLRP1 (NALP1) Nlrp1a-c (Nalp1) NLRP Pro-Caspase-5 Pro-Caspase-1 ASC NLRP1 Danger signals: ATP, NAD , β-amyloid Cardinal ASC NLRP3 Signal 1 Toxins Secretion of Nlrp2, Nlrp3 (Nalp3), Nlrp4a-g ASC NLRP1 and particulates such as calcium pyrophosphate Pannexin-1 Particulate Pro-Caspase-1Pro-Caspase-1 P2X7 Receptor β NLRP2-9 (NALP2-9), (Nalp4a-g), Nlrp5, Nlrp6, Cardinal ASC NLRP3 dihydrate and monosodium urate Activators IL-1 & IL-18 NLRP Pro-Caspase-1ASC NLRP1 NLRP11-14 (NALP11-14) Nlrp9a-c (Nalp9a-c), Nlrp12 Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-5 Xenogenous compounds: Silica, asbestos, and alum (Nalp12), Nlrp14 (Nalp14) Pro-Caspase-1 In uenza virus Endogenous Cytokine Active IL-1β Pro-Caspase-1 Active IL-18 IPAF IPAF Listeria monocytogenes PAMP NLRP10 (NALP10) Nlrp10 (Nalp10) NLRP Pro-Caspase-1Pro-Caspase-1 CardinalPro-Caspase-1ASC NLRP3Pro-Caspase-5 Microbial Ligand 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 ROS NAD FIND CARD Pro-Caspase-1 IPAF CardinalPro-Caspase-1Pro-Caspase-1ASC NLRPPro-Caspase-53 NAD FIND CARD NLRC3NAD (NOD3), FINDNLRC5CARD IPAF Pro-Caspase-1IPAF IPAF Pro-Caspase-5 Sendai virus IL-1 RAcP Phagosome Nlrc3, Nlrc5 NLRC Cardinal ASC NLRP3 (NOD27) ASC Pro-Caspase-5ASC NLRP1Pro-Caspase-1 ASC NLRP1 Staphylococcus aureus x AD NACHT Pro-Caspase-5 Pro-Caspase-1 Pro-Caspase-1Pro-Caspase-1ASC Pro-Caspase-1NLRPPro-Caspase-51 x x Pro-Caspase-1Pro-Caspase-5Pro-Caspase-1NAIP Pro-Caspase-1 x AD NACHT ROS NLRX1 (NOD9)AD NACHT Nlrx1 NLRX Pro-Caspase-5IPAF Pro-Caspase-1 Pro-Caspase-1ASC NAIPNLRP1 AD NACHT IL-1 RI TIR Domain Pro-Caspase-5 Pro-Caspase-1 ASC IPAF NLRP1 Pro-Caspase-1 IPAF (NLRC4) InflASC ammasomePro-Caspase-1NLRP1 Select Microbial Activators Death Domain BIRDOMAIN ORGANIZATION OF RELATEDASC ADAPTORASC PROTEINSPro-Caspase-1NLRP1 PYD Pro-Caspase-5ASC NLRP1Pro-Caspase-1 Pro-Caspase-1 Phagolysosome 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 Toll-like Receptor MyD88 ASC NLRP1 Pro-Caspase-1 TIRAP Pro-Caspase-1 IPAF Pro-Caspase-1Pro-Caspase-1 IPAF Cardinal Pro-Caspase-1Pro-Caspase-1ASC NLRPIPAF3 IPAF MyD88 Cardinal: CARD inhibitor of NFκB-activating ligands (found only in humans) Pro-Caspase-1ASC NLRP1 Pro-Caspase-1 IPAF Pseudomonas aeruginosa TRAM Membrane Perturbations Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-1 ASCPro-Caspase-1IPAF Cardinal ASC NLRP3 Salmonella typhimurium TRIF β Pro-Caspase-1 IPAF Cardinal ASCPro-Caspase-1NLRP3 Mature IL-1 2+ Cardinal ASC CardinalPro-Caspase-1ASCPro-Caspase-1NLRP3IPAF Shigella exneri Pro-Caspase-1ASC NLRPNAIP3 Cardinal ASC IPAF NLRP3 Inflammasome Ca DOMAIN KEY Cardinal ASCASCPro-Caspase-1NLRP3 Cardinal ASC NAIPNLRP3 NLRP3 In ammasome Cardinal ASC NLRP3 Oligomerization Cardinal Pro-Caspase-1ASC NLRP3 Protein-Protein Interacting Domains Cardinal ASC NLRPNAIP3 ASC Pyroptosis Mature IL-18 ASC Cardinal ASC Pro-Caspase-1NLRPNAIP3 MKK Caspase Recruitment Domain (CARD) Pro-Caspase-1 IPAF IPAF Cardinal ASC Pro-Caspase-1NLRPIPAF3 Pro-Caspase-1 ASCPro-Caspase-1AIM2 IPAF/NAIP/Pro-Caspase-1Pro-Caspase-1 Pyrin Domain (PYD) Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-1Pro-Caspase-1Pro-Caspase-1 Pro-Caspase-1Pro-Caspase-1 ASC Pro-Caspase-1IPAF Pro-Caspase-1Pro-Caspase-1IPAF IPAF Pro-Caspase-1 Cytokine Processing 2+ Baculovirus Inhibitor of Apoptosis Repeat Domain (BIR) IPAF Pro-Caspase-1 IPAF IKK Ca Pro-Caspase-1Pro-Caspase-1IPAFIPAF ASC IPAFIPAF IPAF Legionella pneumophila JNK Unknown N-terminal Domain ASCAIM2 ASCPro-Caspase-1IPAF Pro-Caspase-1ASCAIM2 IPAFIPAF IPAF Pro-Caspase-1 Pro-Caspase-5 IPAF Nucleotide-Binding/Oligomerization Domain Pro-Caspase-1 NAIPIPAFIPAF Pro-Caspase-1 Pro-Caspase-5 IPAF Pro-IL-18 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-Caspase-1 IPAF ASCPro-Caspase-1AIM2 IPAFIPAF p38 Pro-IL-1β Pro-Caspase-5 Pro-Caspase-1 ASCPro-Caspase-1 IPAF Pro-Caspase-1 IPAF Active Caspase-1 Microbial Ligand Recognition Domain ASC NAIP ASC NLRPAIM21 Infl ammasome IPAF Select Microbial Activators Proteasome 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 Other Domains ASC NLRP1 Pro-Caspase-1 IPAF Pro-Caspase-1 IκB Pro-Caspase-1 NAIP Pro-Caspase-1 IκB Pro-Caspase-1 IPAFIPAF ASCAIM2 NAIP DS-DNA from virus, bacteria, or the host itself AP-1 NACHT-Associated Domain (NAD) Pro-Caspase-1ASC IPAFIPAF Pro-Caspase-1 IPAF Pro-Caspase-1 Pro-Caspase-1 IPAF Pro-Caspase-1 IPAFIPAF NFκB FunctionPro-Caspase-1 to Find Domain (FIIND) IPAF Pro-Caspase-1ASCAIM2 NFκB Pro-Caspase-1 Pro-Caspase-1 IPAFIPAF Transcription of Activation Domain (AD) Pro-Caspase-1 Pro-Caspase-1ASC IPAF ASC CardinalIPAF ASC NLRP3 IPAF IL-1β and IL-18 ASC Cardinal ASC NLRPOligomerized3 Pro-Caspase-1in ammasome complexes may consist of more subunits than what is shown. Cardinal ASC NLRP3 ASC IPAF Cardinal ASC NLRP3 Pro-Caspase-1ASCASCAIM2 Pro-Caspase-1 This illustration represents general processes suggested in the scienti c literature and is Pro-Caspase-1notASC to be considered comprehensive nor de nitive. ©2010,ASC 2015 R&D Systems Pro-in ammatory Cytokines Pro-Caspase-1 ASC MP_In ammasomes_1550 Pro-Caspase-1ASC ASC Pro-Caspase-1 Pro-Caspase-1 ASC Pro-Caspase-1 ASCAIM2 Pro-Caspase-1 Pro-Caspase-1ASC Pro-Caspase-1 ASCAIM2 Pro-Caspase-1ASCAIM2 Global [email protected] [email protected] Pro-Caspase-1 ASCAIM2 Pro-Caspase-1ASC North America TELASC 800AIM2 343 7475 Pro-Caspase-1 IPAF IPAF Europe | Middle East | Africa TEL +44 (0)1235IPAF 529449 ASCAIM2 LEARN MORE IPAF ASCAIM2 Pro-Caspase-1 China ASCAIM2 rndsystems.com/ [email protected] TEL +86 (21) 52380373 ASCAIM2 Pro-Caspase-1 IPAF ASCAIM2 inflammasome Pro-Caspase-1 Rest of World bio-techne.com/fiPro-Caspase-1 nd-us/distributorsIPAF TEL +1 612 379ASC 2956AIM2 IPAF Pro-Caspase-1 IPAF bio-techne.com 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