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Hornung V, Ablasser A, Charrel-Dennis M et al.AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514-518

Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nature (Impact Factor: 42.35). 02/2009; 458(7237):514-8. DOI: 10.1038/nature07725
Source: PubMed

ABSTRACT 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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    • "Mtb also elicits inflammatory responses, an event that is not mediated by cGAS or STING but by the intracellular inflammasome complex. Interestingly, the inflammasome-mediated host response also relies on the presence of cytosolic DNA, which is sensed by AIM2 (Saiga et al., 2012; Hornung et al., 2009). "
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    ABSTRACT: Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1β (IL-1β) production. Whereas the inflammasome regulates IL-1β secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 06/2015; 17(6). DOI:10.1016/j.chom.2015.05.003 · 12.19 Impact Factor
    • "Of these, AIM2, p204 (also known as Ifi204) and IFI16 have been shown to bind DNA directly via their HIN domains culminating in the production of antiviral and proinflammatory cytokines. Moreover, some members of the PYHIN family (e.g., AIM2 and IFI16) can form inflammasome complexes, resulting in interleukin-1b (IL-1b) processing by caspase-1 (Burckstummer et al., 2009; Fernandes-Alnemri et al., 2009; Hornung et al., 2009; Roberts et al., 2009). In the case of IFI16, this occurs following recognition of Kaposi's sarcomaassociated herpesvirus (KSHV) genomic DNA in the cell nucleus (Kerur et al., 2011). "
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    ABSTRACT: The detection of nucleic acids by the innate immune system is an essential host response during viral infection. In recent years, a number of immune sensors capable of recognizing cytosolic DNA have been identified and include the PYHIN family members AIM2, IFI16, and p204 as well as the enzyme, cGAS. Activation of these receptors leads to the induction of antiviral genes including Type-1 interferons and chemokines such as CCL5. We have carried out extensive expression profiling of these DNA sensors and other members of the PYHIN family in highly purified primary astrocytes and microglia and have demonstrated that both cell types express the majority of these proteins at the mRNA level. In microglia, several family members are highly upregulated in response to IFN-β treatment while both cell types induce robust proinflammatory and antiviral cytokine production (e.g., IL-6, CCL5, IFN-β) in the presence of immune stimulatory DNA and RNA. The production of IL-6 is partially dependent on the interferon receptor as is IFN-β itself. Furthermore, we have found that p204 and AIM2 are upregulated in a Type I IFN dependent fashion in vivo, in a murine model of chronic neurodegeneration. Given the propensity of inflammatory responses to cause neuronal damage, increased expression and activation of these receptors, not only during viral infection but also during sterile inflammatory responses, has the potential to exacerbate existing neuroinflammation leading to further damage and impaired neurogenesis. GLIA 2015
    Glia 01/2015; 63(5). DOI:10.1002/glia.22786 · 6.03 Impact Factor
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    • "ASCforms an adaptor between the CARD domain on caspase-1 and the pyrin domain on NLRP3, NLRC4, or AIM2 (Hornung et al., 2009;Mariathasan et al., 2004). "
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    ABSTRACT: Gardnerella vaginalis is a Gram-positive bacterium associated with bacterial vaginosis (BV), pelvic inflammatory disease, and preterm birth. BV is the most prevalent vaginal infection in women, characterized by the absence of normal Lactobacilli and overgrowth of G. vaginalis and other bacterial species. This study tested the hypothesis that G. vaginalis induces an inflammatory response in the human cell line, THP-1. The objectives of the study were to 1) determine whether different strains of G. vaginalis cause proinflammatory cytokinesproduction in THP-1 cells, 2) characterize intracellular pathways by which these cytokines are produced, and 3) determine molecular mechanisms involved in death of cells treated with strains of G. vaginalis. In these studies, G. vaginalis strain 14018 induced statisticaliy significant increases in the inflammasome-dependent cytokines IL-1β, IL-18, as well as TNF-α in THP-1 monocytes. This same strain of G. vaginalis also caused statistically significant cell death in THP-1 monocytes and cleavage of caspase-1 by 24 h following treatment. Knockdown of the inflammasome component, NLRP3, in THP-1 cells reduced secretion of IL-1β. Additionally, THP-1 cells stably expressing ASC with a fluorescent tag exhibited colocalization of NLRP3 with ASC in G. vaginalis-treated THP-1 cells. These studies confirmed the role of the NLRP3 inflammasome in G. vaginalis inflammation. In a strain-specific study, a statistically significant increase in THP-1 monocyte differentiation and IL-1β secretion were detected in response to G. vaginalis strains 14018 and 49145 but not strain 14019. Cytokine and inflammasome responses were similar for strains 14018 and 49145, but strain 14019 did not induce an inflammatory response in THP-1 cells. The strain-specific ability of G. vaginalis to induce inflammation could con- tribute to the variability observed clinically between women colonized with G. vaginalis. The deleterious effects of G. vaginalis observed in THP-1 monocytes were not observed for the human trophoblast cell line HTR8 when treated with any of the G. vaginalis strains. The results of these studies increase the understanding of how G. vaginal- is activates the innate immune system and suggests that a strain-dependent activation of inflammation may be involved in bacterial vaginosis and preterm birth.
    12/2014, Degree: Ph.D., Supervisor: Anthony Farone
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