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dc.contributor.authorCsak, Timea
dc.contributor.authorPillai, Arun
dc.contributor.authorGanz, Michal
dc.contributor.authorLippai, Dora
dc.contributor.authorPetrasek, Jan
dc.contributor.authorPark, Jin-Kyu
dc.contributor.authorKodys, Karen
dc.contributor.authorDolganiuc, Angela
dc.contributor.authorKurt-Jones, Evelyn A.
dc.contributor.authorSzabo, Gyongyi
dc.date2022-08-11T08:08:37.000
dc.date.accessioned2022-08-23T16:01:14Z
dc.date.available2022-08-23T16:01:14Z
dc.date.issued2014-10-01
dc.date.submitted2014-09-11
dc.identifier.citationLiver Int. 2014 Oct;34(9):1402-13. doi: 10.1111/liv.12537. <a href="http://dx.doi.org/10.1111/liv.12537">Link to article on publisher's site</a>
dc.identifier.issn1478-3223 (Linking)
dc.identifier.doi10.1111/liv.12537
dc.identifier.pmid24650018
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31075
dc.description.abstractBACKGROUND and AIMS: Inflammation promotes the progression of non-alcoholic steatohepatitis (NASH). Toll-like receptor 4 (TLR4) and TLR9 activation through myeloid differentiation primary response gene 88 (MyD88) and production of mature interleukin-1beta (IL-1beta) via inflammasome activation contribute to steatohepatitis. Here, we investigated the inter-relationship between TLR signalling and inflammasome activation in dietary steatohepatitis. METHODS: Wild type (WT), TLR4- and MyD88-deficient (KO) mice received methionine-choline-deficient (MCD) or -supplemented (MCS) diets for 5 weeks and a subset was challenged with TLR9 ligand CpG-DNA. RESULTS: TLR4, TLR9, AIM2 (absent in melanoma 2) and NLRP3 (NLR family pyrin domain containing 3) inflammasome mRNA, and mature IL-1beta protein levels were increased in MCD diet-induced steatohepatitis compared to MCS controls. TLR9 stimulation resulted in greater up-regulation of the DNA-sensing AIM2 expression and IL-1beta production in livers of MCD compared to MCS diet-fed mice. High mobility group box 1 (HMGB1), a TLR9-activating danger molecule and phospho-HMGB1 protein levels were also increased in livers of MCD diet-fed mice. MyD88- but not TLR4-deficiency prevented up-regulation of AIM2, NLRP3 mRNA and IL-1beta protein production in dietary steatohepatitis. Selective MyD88 deficiency either in bone marrow (BM)-derived or non-BM-derived cells attenuated hepatic up-regulation of inflammasome mRNA, caspase-1 activation and IL-1beta protein production, but only BM-derived cell-specific MyD88-deficiency attenuated liver injury. CONCLUSIONS: Our data demonstrate that both bone marrow-derived and non-BM-derived cells contribute to inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis. We show that AIM2 inflammasome expression and activation are further augmented by TLR9 ligands in dietary steatohepatitis.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24650018&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1111/liv.12537
dc.subjectDigestive System Diseases
dc.subjectGastroenterology
dc.subjectGenomics
dc.subjectHepatology
dc.subjectImmunopathology
dc.titleBoth bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis
dc.typeJournal Article
dc.source.journaltitleLiver international : official journal of the International Association for the Study of the Liver
dc.source.volume34
dc.source.issue9
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gastroenterology_pp/131
dc.identifier.contextkey6105457
html.description.abstract<p>BACKGROUND and AIMS: Inflammation promotes the progression of non-alcoholic steatohepatitis (NASH). Toll-like receptor 4 (TLR4) and TLR9 activation through myeloid differentiation primary response gene 88 (MyD88) and production of mature interleukin-1beta (IL-1beta) via inflammasome activation contribute to steatohepatitis. Here, we investigated the inter-relationship between TLR signalling and inflammasome activation in dietary steatohepatitis.</p> <p>METHODS: Wild type (WT), TLR4- and MyD88-deficient (KO) mice received methionine-choline-deficient (MCD) or -supplemented (MCS) diets for 5 weeks and a subset was challenged with TLR9 ligand CpG-DNA.</p> <p>RESULTS: TLR4, TLR9, AIM2 (absent in melanoma 2) and NLRP3 (NLR family pyrin domain containing 3) inflammasome mRNA, and mature IL-1beta protein levels were increased in MCD diet-induced steatohepatitis compared to MCS controls. TLR9 stimulation resulted in greater up-regulation of the DNA-sensing AIM2 expression and IL-1beta production in livers of MCD compared to MCS diet-fed mice. High mobility group box 1 (HMGB1), a TLR9-activating danger molecule and phospho-HMGB1 protein levels were also increased in livers of MCD diet-fed mice. MyD88- but not TLR4-deficiency prevented up-regulation of AIM2, NLRP3 mRNA and IL-1beta protein production in dietary steatohepatitis. Selective MyD88 deficiency either in bone marrow (BM)-derived or non-BM-derived cells attenuated hepatic up-regulation of inflammasome mRNA, caspase-1 activation and IL-1beta protein production, but only BM-derived cell-specific MyD88-deficiency attenuated liver injury.</p> <p>CONCLUSIONS: Our data demonstrate that both bone marrow-derived and non-BM-derived cells contribute to inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis. We show that AIM2 inflammasome expression and activation are further augmented by TLR9 ligands in dietary steatohepatitis.</p>
dc.identifier.submissionpathgastroenterology_pp/131
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.source.pages1402-13


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