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      IFI16 is involved in HBV-associated acute-on-chronic liver failure inflammation

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          Abstract

          Background

          Hepatitis B virus (HBV) is a hepatotropic DNA virus, and its DNA may be a potent inflammatory molecule. Interferon-inducible protein 16 (IFI16), a newly discovered DNA sensor, plays an important role in the process of inflammation in viral infections. Our study sought to identify a correlation between IFI16 expression and inflammation in patients with chronic hepatitis B (CHB) and HBV-associated acute-on-chronic liver failure (HBV-ACLF).

          Methods

          We performed flow cytometry to measure IFI16 levels in peripheral blood mononuclear cells (PBMC) and used immunohistochemistry and western blotting to measure IFI16 protein levels in liver tissues. The cellular source of IFI16 was detected using double immunofluorescence. All datum were analyzed using SPSS 13.0 and GraphPad Prism 6.

          Results

          The number of IFI16+ cells was significantly associated with the degree of inflammation. In detail, the number of IFI16+ cells was higher in livers but lower in PBMCs in HBV-ACLF patients than those in CHB patients and healthy controls. There was no significant difference between CHB patients and healthy controls in numbers of IFI6+ cells in livers and PBMCs. There was no significant relationship between IFI16 expression levels and HBV parameters. Furthermore, IFI16 was expressed in the nucleus of Kupffer cells (KCs), endothelial cells, natural killer cells, dendritic cells, and hepatic stellate cells in healthy donors and CHB patients, but only in the cytoplasm of KCs in the livers of HBV-ACLF patients.

          Conclusions

          IFI16 was closely related to the degree of inflammation in CHB and HBV-ACLF patients and may serve as a vital contributor to the pathogeneses of liver damage in HBV-ACLF.

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          Most cited references16

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          IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.

          Inflammasomes are cytoplasmic sensors of foreign molecules, including pathogens, and function to induce caspase-1 activation and IL-1β cytokine maturation. Whether such a mechanism exists in the nucleus and is effective against nuclear replicating pathogens is unknown. Nuclear replicating herpesvirus KSHV is associated with Kaposi Sarcoma, an angioproliferative tumor characterized by an inflammatory microenvironment including IL-1β. We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome. This complex was initially detected in the nucleus and subsequently in the perinuclear area. KSHV gene expression and/or latent KSHV genome is required for inflammasome activation and IFI16 colocalizes with the KSHV genome in the infected cell nucleus. Caspase-1 activation by KSHV was reduced by IFI16 and ASC silencing. Our studies reveal IFI16 as a nuclear pathogen sensor and demonstrate that the inflammasome also functions in the nucleus. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection.

            Knowledge of the immunological events necessary to control hepatitis B virus (HBV) infection has accelerated in recent years, but their translation towards therapeutic strategies able to achieve a durable HBV suppression has been challenging. The scenario of how HBV deals with the host immunity is presented and used to discuss how the immune response can be harnessed to potentially achieve infection control.
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              Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes.

              Inflammasomes are multiprotein complexes that recognize pathogens and pathogen- or danger-associated molecular patterns. They induce the maturation and secretion of powerful proinflammatory interleukin-1B (IL-1β), IL-18, and IL-33 cytokines, which in turn activate expression of other immune genes and lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Inflammasomes are comprised of cytoplasmic sensor molecules, such as NLRP3 and AIM2 or nuclear sensor IFI16, the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD), and the effector protein procaspase-1. Herpes simplex virus 1 (HSV-1), a ubiquitous virus that infects humans and establishes life-long latency, has evolved numerous mechanisms to evade host detection and immune responses. Here, we show that early during in vitro infection of human foreskin fibroblasts (2 to 4 h), HSV-1 induced the activation of the IFI16 and NLRP3 inflammasomes and maturation of IL-1β. Independent of viral gene expression, IFI16 recognized the HSV-1 genome in infected cell nuclei, relocalized, and colocalized with ASC in the cytoplasm. However, HSV-1 specifically targeted IFI16 for rapid proteasomic degradation at later times postinfection, which was dependent on the expression of ICP0, an immediate early protein of HSV-1. In contrast, NLRP3, AIM2, and ASC levels were not decreased. Also, caspase-1 was "trapped" in actin clusters at later time points that likely blocked the NLRP3/IFI16 inflammasome activity. In addition, the secretion of mature IL-1β was inhibited. These results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSV-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.
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                Author and article information

                Contributors
                +86 20 85252373 , xdy-gz@163.com
                +86 20 85252373 , gaozhl@mail.sysu.edu.cn
                Journal
                BMC Gastroenterol
                BMC Gastroenterol
                BMC Gastroenterology
                BioMed Central (London )
                1471-230X
                9 May 2018
                9 May 2018
                2018
                : 18
                : 61
                Affiliations
                [1 ]Department of Infectious Diseases, Third Affiliated Hospital of Sun-Yat-SenUniversity, GuangZhou, China
                [2 ]ISNI 0000 0004 1762 1794, GRID grid.412558.f, GuangDong Provincial Key Laboratory of Liver Disease, , Third Affiliated Hospital of Sun-Yat-Sen University, ; GuangZhou, China
                [3 ]ISNI 0000 0004 1762 1794, GRID grid.412558.f, Department of Pathology, , Third Affiliated Hospital of Sun-Yat-Sen University, ; GuangZhou, China
                [4 ]GuangZhou, China
                Author information
                http://orcid.org/0000-0003-1726-024X
                Article
                791
                10.1186/s12876-018-0791-1
                5944170
                29743020
                12c89867-5f17-4b64-9ca2-4fcbf373a6df
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 January 2018
                : 30 April 2018
                Funding
                Funded by: National Science and Technology Major Project
                Award ID: 2016ZX10002003
                Award ID: 2016ZX10002008
                Award ID: 2016ZX10002009
                Award Recipient :
                Funded by: Natural Science Fund of Guangdong Province
                Award ID: 2015A030313022
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Gastroenterology & Hepatology
                ifn inducible protein 16 (ifi16),chronic hepatitis b (chb),hbv-associated acute-on-chronic liver failure (hbv-aclf),inflammation

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