title: Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis.
abstract: OBJECTIVE
  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-1β (IL-1β) 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-1β 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-1β 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-1β 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-1β 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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.forename: Arun
authors.initials: A
authors.lastname: Pillai
authors.forename: Michal
authors.initials: M
authors.lastname: Ganz
authors.forename: Dora
authors.initials: D
authors.lastname: Lippai
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Park
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002796:Choline Deficiency; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004032:Diet; D005786:Gene Expression Regulation / Q000502:physiology*; D047468:Immunoprecipitation; D058847:Inflammasomes / Q000378:metabolism*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D008715:Methionine
keywords: AIM2; HMGB1; IL-1β; MyD88; NLRP3; TLR4; TLR9; caspase-1; inflammasome; non-alcoholic steatohepatitis