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TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival.
Clin Sci (Lond). 2017 Aug 15; 131(16):2145-2159.CS

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 pro-inflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis.

Authors+Show Affiliations

Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.Department of Pathology, University of Washington, Seattle, WA, U.S.A.Department of Medicine/Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, U.S.A.Department of Medicine/Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, U.S.A.Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.School of Surgery, University of Western Australia, Perth, WA, Australia.Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia geoff.farrell@anu.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28687713

Citation

Mridha, Auvro R., et al. "TLR9 Is Up-regulated in Human and Murine NASH: Pivotal Role in Inflammatory Recruitment and Cell Survival." Clinical Science (London, England : 1979), vol. 131, no. 16, 2017, pp. 2145-2159.
Mridha AR, Haczeyni F, Yeh MM, et al. TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival. Clin Sci. 2017;131(16):2145-2159.
Mridha, A. R., Haczeyni, F., Yeh, M. M., Haigh, W. G., Ioannou, G. N., Barn, V., Ajamieh, H., Adams, L., Hamdorf, J. M., Teoh, N. C., & Farrell, G. C. (2017). TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival. Clinical Science (London, England : 1979), 131(16), 2145-2159. https://doi.org/10.1042/CS20160838
Mridha AR, et al. TLR9 Is Up-regulated in Human and Murine NASH: Pivotal Role in Inflammatory Recruitment and Cell Survival. Clin Sci. 2017 Aug 15;131(16):2145-2159. PubMed PMID: 28687713.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival. AU - Mridha,Auvro R, AU - Haczeyni,Fahrettin, AU - Yeh,Matthew M, AU - Haigh,W Geoffrey, AU - Ioannou,George N, AU - Barn,Vanessa, AU - Ajamieh,Hussam, AU - Adams,Leon, AU - Hamdorf,Jeffrey M, AU - Teoh,Narci C, AU - Farrell,Geoffrey C, Y1 - 2017/07/24/ PY - 2016/11/07/received PY - 2017/06/14/revised PY - 2017/07/06/accepted PY - 2017/7/9/pubmed PY - 2017/9/7/medline PY - 2017/7/9/entrez KW - Toll-like receptors KW - bone marrow macrophages KW - inflammation KW - innate immunity KW - necroptosis KW - non alcoholic fatty liver disease SP - 2145 EP - 2159 JF - Clinical science (London, England : 1979) JO - Clin. Sci. VL - 131 IS - 16 N2 - : 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 pro-inflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/28687713/TLR9_is_up_regulated_in_human_and_murine_NASH:_pivotal_role_in_inflammatory_recruitment_and_cell_survival_ L2 - https://portlandpress.com/clinsci/article-lookup/doi/10.1042/CS20160838 DB - PRIME DP - Unbound Medicine ER -