RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Csak, Timea  Pillai, Arun  Ganz, Michal  Lippai, Dora  Petrasek, Jan  Park, Jin-Kyu  Kodys, Karen  Dolganiuc, Angela  Kurt-Jones, Evelyn A  Szabo, Gyongyi 
Citation: Csak T, etal., Liver Int. 2014 Oct;34(9):1402-13. doi: 10.1111/liv.12537. Epub 2014 Apr 17.
RGD ID: 18337469
Pubmed: PMID:24650018   (View Abstract at PubMed)
PMCID: PMC4169310   (View Article at PubMed Central)
DOI: DOI:10.1111/liv.12537   (Journal Full-text)


BACKGROUND & 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-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.




  
Object Symbol
Species
Term
Qualifier
Evidence
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Original Reference(s)
TLR9Humanmetabolic dysfunction-associated steatohepatitis disease_progressionISORGD:1549988mRNA, protein:increased expression:serum, liver (mouse)RGD 
Tlr9Ratmetabolic dysfunction-associated steatohepatitis disease_progressionISORGD:1549988mRNA, protein:increased expression:serum, liver (mouse)RGD 
Tlr9Mousemetabolic dysfunction-associated steatohepatitis disease_progressionIEP mRNA, protein:increased expression:serum, liver (mouse)RGD 


Genes (Rattus norvegicus)
Tlr9  (toll-like receptor 9)

Genes (Mus musculus)
Tlr9  (toll-like receptor 9)

Genes (Homo sapiens)
TLR9  (toll like receptor 9)