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- Title
TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival.
- Authors
Mridha, Auvro R.; Haczeyni, Fahrettin; Yeh, Matthew M.; Haigh, W. Geoffrey; Ioannou, George N.; Barn, Vanessa; Ajamieh, Hussam; Adams, Leon; Hamdorf, Jeffrey M.; Teoh, Narci C.; Farrell, Geoffrey C.
- Abstract
Background and aims: TLR9 deletion protects against steatohepatitis due to choline--amino acid depletion and high-fat diet. We measured TLR9 in human non-alcoholic steatohepatitis (NASH) livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of non-alcoholic fatty liver disease (NAFLD). Methods: We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wild-type (Wt), appetite-dysregulated Alms1 mutant (foz/foz), Tlr9-/-, and Tlr9-/-.foz/foz C57BL6/J mice and bone marrow (BM) chimeras were fed 0.2% cholesterol, high-fat, high sucrose (atherogenic[Ath]) diet or chow, and NAFLD activity score (NAS)/NASH pathology, macrophage/neutrophil infiltration, cytokines/chemokines, and cell death markers measured in livers. Results: Hepatic TLR9 and TLR4 mRNA were increased in human NASH but not simple steatosis, and in Ath-fed foz/foz mice with metabolic syndrome-related NASH. Ath-fed Tlr9-/- mice showed simple steatosis and less Th1 cytokines than Wt. Tlr9-/-.foz/foz mice were obese and diabetic, but necroinflammatory changes were less severe than Tlr9+/+.foz/foz mice. TLR9-expressing myeloid cells were critical for Th1 cytokine production in BM chimeras. BM macrophages from Tlr9-/- mice showed M2 polarization, were resistant to M1 activation by necrotic hepatocytes/other pro-inflammatory triggers, and provoked less neutrophil chemotaxis than Wt. Livers from Ath-fed Tlr9-/- mice appeared to exhibit more markers of necroptosis [receptor interacting protein kinase (RIP)-1, RIP-3, and mixed lineage kinase domain-like protein (MLKL)] than Wt, and ~25% showed portal foci of mononuclear cells unrelated to NASH pathology. Conclusion: Our novel clinical data and studies in overnutrition models, including those with diabetes and metabolic syndrome, clarify TLR9 as a proinflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis.
- Subjects
FATTY liver; CHOLINE; AMINO acids in nutrition; HIGH-fat diet; INFLAMMATION
- Publication
Clinical Science, 2017, Vol 131, Issue 16, p2145
- ISSN
0143-5221
- Publication type
Article
- DOI
10.1042/CS20160838