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      Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin‐induced liver fibrosis and biliary fibrosis in mice

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          Abstract

          Although numerous studies have suggested that canonical IκB kinases (IKK) play a key role in the progression of liver fibrosis, the role of non‐canonical IKKε and TANK‐binding kinase 1 (TBK1) on the development and progression of liver fibrosis remains unclear. To demonstrate such issue, repeated injection of CCl 4 was used to induce hepatotoxin‐mediated chronic liver injury and biliary fibrosis was induced by 0.1% diethoxycarbonyl‐1, 4‐dihydrocollidine diet feeding for 4 weeks. Mice were orally administered with amlexanox (25, 50, and 100 mg/kg) during experimental period. Significantly increased levels of TBK1 and IKKε were observed in fibrotic livers or hepatic stellate cells (HSCs) isolated from fibrotic livers. Interestingly, amlexanox treatment significantly inhibited the phosphorylation of TBK1 and IKKε accompanied by reduced liver injury as confirmed by histopathologic analysis, decreased serum biochemical levels and fibro‐inflammatory responses. Additionally, treatment of amlexanox promoted the fibrosis resolution. In accordance with these findings, amlexanox treatment suppressed HSC activation and its related fibrogenic responses by partially inhibiting signal transducer and activator of transcription 3. Furthermore, amlexanox decreased the activation and inflammatory responses in Kupffer cells. Collectively, we found that inhibition of the TBK1 and IKKε by amlexanox is a promising therapeutic strategy to cure liver fibrosis.

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          Most cited references31

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          Triggering the interferon antiviral response through an IKK-related pathway.

          Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor kappaB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.
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            An inhibitor of the protein kinases TBK1/IKKε improves obesity-related metabolic dysfunctions

            Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKKε and TANK-binding kinase 1 (TBK1) are induced in liver and fat after high fat diet by NF-κB activation, and in turn initiate a program of counter-inflammation that preserves energy storage. Here, we report the discovery of a small molecule inhibitor of these kinases called amlexanox. Treatment of obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis in obese mice. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders.
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              TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation

              LUBAC modulates signalling by various immune receptors. In TNF signalling, linear (also known as M1) ubiquitin enables full gene-activation and prevents cell death. However, the mechanisms underlying cell-death prevention remain ill-defined. We show that LUBAC activity enables TBK1 and IKKε recruitment to and activation at the TNFR1-signalling complex (TNFR1-SC). Whilst exerting only limited effects on TNF-induced gene-activation, TBK1/IKKε are essential to prevent TNF-induced cell death. Mechanistically, TBK1/IKKε phosphorylate RIPK1 in the TNFR1-SC, thereby preventing RIPK1-kinase-activity-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO/IKKγ, which mostly, but not exclusively, binds to the TNFR1-SC via M1-ubiquitin, mediates recruitment of the adaptors TANK and NAP1/AZI2 which are constitutively associated with TBK1/IKKε and TBK1, respectively. We here discover a previously unrecognised TBK1/IKKε-mediated cell-death checkpoint and uncover an essential survival function for NEMO by enabling recruitment and activation of these noncanonical IKKs to prevent TNF-induced cell death.
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                Author and article information

                Contributors
                kjw@jbnu.ac.kr
                bskims@jbnu.ac.kr
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                10 December 2019
                January 2020
                : 24
                : 2 ( doiID: 10.1111/jcmm.v24.2 )
                : 1383-1398
                Affiliations
                [ 1 ] Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program) College of Veterinary Medicine Jeonbuk National University Iksan Korea
                Author notes
                [*] [* ] Correspondence

                Bumseok Kim and Jong‐Won Kim, Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk 54596, South Korea.

                Email: bskims@ 123456jbnu.ac.kr (BK); kjw@ 123456jbnu.ac.kr (J‐WK)

                Author information
                https://orcid.org/0000-0003-0392-2513
                Article
                JCMM14817
                10.1111/jcmm.14817
                6991653
                31821710
                bedc9f0c-4515-42c4-a3c2-a71caec7d4da
                © 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 July 2019
                : 23 September 2019
                : 26 October 2019
                Page count
                Figures: 7, Tables: 1, Pages: 16, Words: 7957
                Funding
                Funded by: Ministry of Education, Republic of Korea , open-funder-registry 10.13039/501100002701;
                Award ID: 2017R1A6A3A11032024
                Award ID: NRF‐2017R1D1A3B03030521
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:30.01.2020

                Molecular medicine
                amlexanox,hepatic stellate cells (hscs),liver fibrosis,mice
                Molecular medicine
                amlexanox, hepatic stellate cells (hscs), liver fibrosis, mice

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