Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.
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PMID:AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. 1915 75

Host- and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome, which activates caspase-1 leading to maturation of pro-interleukin-1beta and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain, senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome, which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.
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PMID:AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. 1915 76

Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1beta and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1beta and IL-18 from pro-IL-1beta and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.
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PMID:Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. 1947 96

NLRP1 (NLR family, pyrin domain-containing 1) is a contributor to innate immunity involved in intracellular sensing of pathogens, as well as danger signals related to cell injury. NLRP1 is one of the core components of caspase-1-activating platforms termed "inflammasomes," which are involved in proteolytic processing of interleukin-1beta (IL-1beta) and in cell death. We previously discovered that anti-apoptotic proteins Bcl-2 and Bcl-X(L) bind to and inhibit NLRP1 in cells. Using an in vitro reconstituted system employing purified recombinant proteins, we studied the mechanism by which Bcl-2 and Bcl-X(L) inhibit NLRP1. Bcl-2 and Bcl-X(L) inhibited caspase-1 activation induced by NLRP1 in a concentration-dependent manner, with K(i) approximately 10 nM. Bcl-2 and Bcl-X(L) were also determined to inhibit ATP binding to NLRP1, which is required for oligomerization of NLRP1, and Bcl-X(L) was demonstrated to interfere with NLRP1 oligomerization. Deletion of the flexible loop regions of Bcl-2 and Bcl-X(L), which are located between the first and second alpha-helices of these anti-apoptotic proteins and which were previously shown to be required for binding NLRP1, abrogated ability to inhibit caspase-1 activation, ATP binding and oligomerization of NLRP1. Conversely, synthetic peptides corresponding to the loop region of Bcl-2 were sufficient to potently inhibit NLRP1. These findings thus demonstrate that the loop domain is necessary and sufficient to inhibit NLRP1, providing insights into the mechanism by which anti-apoptotic proteins Bcl-2 and Bcl-X(L) inhibit NLRP1.
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PMID:Mechanism of Bcl-2 and Bcl-X(L) inhibition of NLRP1 inflammasome: loop domain-dependent suppression of ATP binding and oligomerization. 1922 83

Urticarial rash observed in cryopyrin-associated periodic syndrome (CAPS) caused by nucleotide-binding oligomerization domain-leucine-rich repeats containing pyrin domain 3 (NLRP3) mutations is effectively suppressed by anti-interleukin (IL)-1 treatment, suggesting a pathophysiological role of IL-1beta in the skin. However, the cellular mechanisms regulating IL-1beta production in the skin of CAPS patients remain unclear. We identified mast cells (MCs) as the main cell population responsible for IL-1beta production in the skin of CAPS patients. Unlike normal MCs that required stimulation with proinflammatory stimuli for IL-1beta production, resident MCs from CAPS patients constitutively produced IL-1beta. Primary MCs expressed inflammasome components and secreted IL-1beta via NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain when stimulated with microbial stimuli known to activate caspase-1. Furthermore, MCs expressing disease-associated but not wild-type NLRP3 secreted IL-1beta and induced neutrophil migration and vascular leakage, the histological hallmarks of urticarial rash, when transplanted into mouse skin. Our findings implicate MCs as IL-1beta producers in the skin and mediators of histamine-independent urticaria through the NLRP3 inflammasome.
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PMID:Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria. 1936 81

Traumatic brain injury elicits acute inflammation that in turn exacerbates primary brain damage. A crucial part of innate immunity in the immune privileged central nervous system involves production of proinflammatory cytokines mediated by inflammasome signaling. Here, we show that the nucleotide-binding, leucine-rich repeat pyrin domain containing protein 1 (NLRP1) inflammasome consisting of NLRP1, caspase-1, caspase-11, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), the X-linked inhibitor of apoptosis protein, and pannexin 1 is expressed in neurons of the cerebral cortex. Moderate parasagittal fluid-percussion injury (FPI) induced processing of interleukin-1beta, activation of caspase-1, cleavage of X-linked inhibitor of apoptosis protein, and promoted assembly of the NLRP1 inflammasome complex. Anti-ASC neutralizing antibodies administered immediately after fluid-percussion injury to injured rats reduced caspase-1 activation, X-linked inhibitor of apoptosis protein cleavage, and processing of interleukin-1beta, resulting in a significant decrease in contusion volume. These studies show that the NLRP1 inflammasome constitutes an important component of the innate central nervous system inflammatory response after traumatic brain injury and may be a novel therapeutic target for reducing the damaging effects of posttraumatic brain inflammation.
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PMID:Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. 1940 9

Despite being used for more than 80 years, the mechanisms of induction of immune responses by aluminum adjuvants, generically referred to as 'alum', remain largely unknown. However, substantial amounts of recently gathered data demonstrate that aluminum salts induce an innate immune reaction at the site of vaccination. Thus, aluminum salts activate dendritic cells, monocytes and macrophages with enhanced expression of adhesion molecules CD54 and CD58 and co-stimulatory molecules CD40 and CD86, which are crucial in T cell activation; induce chemokines CCL2, CCL3, CCL4 and CXCL8, which mediate recruitment of inflammatory cells at the site of vaccination; and stimulate cytokines crucial in the innate immune response. Aluminum adjuvants activate the nucleotide-binding domain and leucine-rich-repeat-containing gene family pyrin-domain-containing 3 (known as NLRP3 or NALP3) inflammasome to activate caspase-1 and to induce proinflammatory cytokines interleukin (IL)-1beta and IL-18 by innate cells. Aluminum adjuvants activate NLRP3 by multiple mechanisms such as by causing damage and rupture of the phagolysosomes, generating reactive oxygen species, inducing K(+) efflux and via release from injured tissues of molecules that constitute danger-associated molecular patterns (DAMPs) such as uric acid and ATP. These novel cellular and molecular mechanisms of aluminum salts are likely to influence how we design effective and safe adjuvants in the future.
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PMID:Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants. 1943 72

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder characterized by seemingly unprovoked recurrent episodes of fever and serosal, synovial, or cutaneous inflammation. FMF is caused by recessively inherited mutations in MEFV, which encodes pyrin, and most of the mutations are present in the C-terminal end of the protein encoding B30.2 domain. The FMF carrier frequencies are extremely high in several eastern Mediterranean populations. Pyrin is expressed in granulocytes, monocytes, dendritic cells, and synovial fibroblasts. Pyrin regulates caspase-1 activation and consequently interleukin-1beta production through the interactions of its N-terminal PYRIN domain and C-terminal B30.2 domain with an adaptor protein, apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC) and caspase-1 respectively. Pyrin is cleaved by caspase-1 and the cleaved N-terminal fragment translocates to nucleus and enhances ASC-independent nuclear factor (NF)-kappaB activation through interactions with p65 NF-kappaB and IkappaB-alpha. In addition to the regulatory role of pyrin for caspase-1, the cleavage of pyrin provides an important clue not only in understanding the molecular pathogenesis of FMF but also in developing new therapeutic targets for FMF.
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PMID:Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. 1946 78

Relative to monocytes, human macrophages are deficient in their ability to process and release IL-1beta. In an effort to explain this difference, we used a model of IL-1beta processing and release that is dependent upon bacterial escape into the cytosol. Fresh human blood monocytes were compared with monocyte-derived macrophages (MDM) for their IL-1beta release in response to challenge with Francisella novicida. Although both cell types produced similar levels of IL-1beta mRNA and intracellular pro-IL-1beta, only monocytes readily released processed mature IL-1beta. Baseline mRNA expression profiling of candidate genes revealed a remarkable deficiency in the pyrin gene, MEFV, expression in MDM compared with monocytes. Immunoblots confirmed a corresponding deficit in MDM pyrin protein. To determine whether pyrin levels were responsible for the monocyte/MDM difference in mature IL-1beta release, pyrin expression was knocked down by nucleofecting small interfering RNA against pyrin into monocytes or stably transducing small interfering RNA against pyrin into the monocyte cell line, THP-1. Pyrin knockdown was associated with a significant drop in IL-1beta release in both cell types. Importantly, M-CSF treatment of MDM restored pyrin levels and IL-1beta release. Similarly, the stable expression of pyrin in PMA-stimulated THP-1-derived macrophages induces caspase-1 activation, associated with increased IL-1beta release after infection with F. novicida. In summary, intracellular pyrin levels positively regulate MDM IL-1beta responsiveness to Francisella challenge.
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PMID:Pyrin critical to macrophage IL-1beta response to Francisella challenge. 1949 23

In acute inflammation, extracellular ATP activates P2X(7) ion channel receptors (P2X(7)R) on M1 polarized macrophages to release pro-inflammatory IL-1beta through activation of the caspase-1/nucleotide-binding domain and leucine-rich repeat receptor containing pyrin domain 3 (NLRP3) inflammasome. In contrast, M2 polarized macrophages are critical to the resolution of inflammation but neither actions of P2X(7)R on these macrophages nor mechanisms by which macrophages switch from pro-inflammatory to anti-inflammatory phenotypes are known. Here, we investigated extracellular ATP signalling over a dynamic macrophage polarity gradient from M1 through M2 phenotypes. In macrophages polarized towards, but not at, M2 phenotype, in which intracellular IL-1beta remains high and the inflammasome is intact, P2X(7)R activation selectively uncouples to the NLRP3-inflammasome activation but not to upstream ion channel activation. In these intermediate M1/M2 polarized macrophages, extracellular ATP now acts through its pyrophosphate chains, independently of other purine receptors, to inhibit IL-1beta release by other stimuli through two independent mechanisms: inhibition of ROS production and trapping of the inflammasome complex through intracellular clustering of actin filaments.
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PMID:Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1beta release through pyrophosphates. 1953 33


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