Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice

Luo, Xiaohua; Li, Honggui; Ma, Linqiang; Zhou, Jing; Guo, Xin; Woo, Shih Lung; Pei, Ya; Knight, Linda R.; Deveau, Michael A.; Chen, Yanming; Qian, Xiaoxian; Xiao, Xiaoqiu; Li, Qifu; Chen, Xiang‐Bai; Huo, Yuqing; McDaniel, Kelly; Francis, Heather; Glaser, Shannon; Meng, Fanyin; Alpini, Gianfranco; Wu, Chaodong

doi:10.1053/j.gastro.2018.09.010

Cited by 286 publications

(342 citation statements)

References 45 publications

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“…For example, Tmem173 (also known as stimulator of interferon genes [STING]) expression was significantly increased in livers of mice with NASH as compared with mice with isolated steatosis in our study (Figure D), promoting us to hypothesize that targeting STING might be a good way to prevent NASH progression. Consistently, three studies published very recently provided various evidence to prove that activation of STING pathway contributes to liver inflammation and the progression of NASH . In addition, we observed that the mRNA of stearoyl‐CoA desaturases 1 ( Scd1 ) was significantly higher in mice with NASH (Figure D), which was consistent with the previous study that overexpression of SCD aggregated while pharmacological inhibitors of SCD attenuated liver fibrosis .…”

Section: Discussionsupporting

confidence: 92%

“…Consistently, three studies published very recently provided various evidence to prove that activation of STING pathway contributes to liver inflammation and the progression of NASH. [32][33][34] In addition, we observed that the mRNA of stearoyl-CoA desaturases 1 (Scd1) was significantly higher in mice with NASH ( Figure 3D), which was consistent with the previous study that overexpression of SCD aggregated while pharmacological inhibitors of SCD attenuated liver fibrosis. 35 We have several more potential targets selected from the transcriptome results are being investigated currently.…”

Section: Bril F Et Al Revealed That Tg Accumulation In Livers Of Patisupporting

confidence: 91%

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Coordinated changes of gut microbiome and lipidome differentiates nonalcoholic steatohepatitis (NASH) from isolated steatosis

Qian

Yao

et al. 2019

Liver International

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Background & Aims Nonalcoholic fatty liver disease encompasses isolated steatosis or nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). NASH develops from isolated steatosis with obscure driving forces. We aim to identify key factors promoting this transition. Methods Following 21‐week of high‐fat diet feeding, obese mice were classified into two groups termed as isolated steatosis and NASH based on hematoxylin‐eosin staining of liver histology. The integrated multi‐omics analysis of lipidome, transcriptome and gut microbiome were performed in mice with isolated steatosis and NASH, and confirmed in human samples. Results Livers in mice with NASH lost most lipids, and the transcriptional landscape was also changed dramatically in mice with NASH in relative to mice with isolated steatosis. Plasma lipidome analysis demonstrated a very clear difference between these two groups of mice, which was partially recapitulated in serum of patients with isolated steatosis and NASH. The microbiota composition revealed that Bacteroides genus and Bacteroides uniformis species decreased while Mucispirillum genus and Mucispirillum schaedleri species increased largely in mice with NASH. More importantly, we found that Bacteroides uniformis correlated positively with triglycerides (TGs) and negatively with free fatty acids (FFAs) and PE(18:1/20:4), while Mucispirillum schaedleri correlated positively with FFAs, LysoPC(20:3), LysoPC(20:4) and DG(16:1/18:2). Mechanically, administration of Bacteroides uniformis increased specific TGs, and decreased hepatic injury and inflammation in diet‐induced mice. Conclusions Overall, through multi‐omics integration, we identified a microbiota‐lipid axis promoting the initiation of NASH from isolated steatosis, which might provide a novel perspective on NASH pathogenesis and treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Bril F Et Al Revealed That Tg Accumulation In Livers Of Patisupporting

confidence: 91%

Coordinated changes of gut microbiome and lipidome differentiates nonalcoholic steatohepatitis (NASH) from isolated steatosis

Qian

Yao

et al. 2019

Liver International

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“…Total levels of STAT3 were elevated, but not in its activated phosphorylated form (pY705), which regulates gene transcription for modulation of immunosuppressive factors . The expression of STING suggests a macrophage‐mediated hepatic inflammation and fibrogenic process .…”

Section: Resultsmentioning

confidence: 99%

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Figueiredo

Kalirai

Sacco

et al. 2020

The Journal of Pathology

109

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Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour‐infiltrating lymphocytes (TILs) within pUM and surrounding mUM – and some evidence of clinical responses to adoptive TIL transfer – strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA‐DR, CD38, and CD74. Further, single‐cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour‐associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD‐L1, and β‐catenin (CTNNB1), suggesting tumour‐driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 − mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…IRF3 can also be activated by stimulator of interferon genes (STING). However, activation of STING promotes both inflammation and injury . Interestingly, in other model systems, STING is both activated by endoplasmic reticulum (ER) stress and induces ER stress .…”

Section: Discussionmentioning

confidence: 99%

“…However, activation of STING promotes both inflammation and injury. (34) Interestingly, in other model systems, STING is both activated by endoplasmic reticulum (ER) stress (17) and induces ER stress. (35) This relation to ER stress may contribute to the proinflammatory effects of this pathway in HFD-induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

Nontranscriptional Activity of Interferon Regulatory Factor 3 Protects Mice From High‐Fat Diet‐Induced Liver Injury

Sanz‐Garcia¹,

McMullen²,

Chattopadhyay³

et al. 2019

Hepatol Commun

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Interferon regulatory factor 3 (IRF3) has both transcriptional and nontranscriptional functions. Transcriptional activity is dependent on serine phosphorylation of IRF3, while transcription‐independent IRF3‐mediated apoptosis requires ubiquitination. IRF3 also binds to inhibitor of nuclear factor kappa B kinase (IKKβ) in the cytosol, restricting nuclear translocation of p65. IRF3‐deficient mice are highly sensitive to high‐fat diet (HFD)‐induced liver injury; however, it is not known if transcriptional and/or nontranscriptional activity of IRF3 confers protection. Using a mouse model only expressing nontranscriptional functions of IRF3 (Irf3S1/S1), we tested the hypothesis that nontranscriptional activity of IRF3 protects mice from HFD‐induced liver injury. C57BL/6, Irf3−/−, and Irf3S1/S1 mice were fed an HFD for 12 weeks. In C57BL/6 mice, the HFD increased expression of interferon (IFN)‐dependent genes, despite a decrease in IRF3 protein in the liver. The HFD had no impact on IFN‐dependent gene expression Irf3−/− or Irf3S1/S1 mice, both lacking IRF3 transcriptional activity. Liver injury, apoptosis, and fibrosis were exacerbated in Irf3−/− compared to C57BL/6 mice following the HFD; this increase was ameliorated in Irf3S1/S1 mice. Similarly, expression of inflammatory cytokines as well as numbers of neutrophils and infiltrating monocytes was increased in Irf3−/− mice compared to C57BL/6 and Irf3S1/S1 mice. While the HFD increased the ubiquitination of IRF3, a response associated with IRF3‐mediated apoptosis, in Irf3S1/S1 mice, protection from liver injury was not due to differences in apoptosis of hepatocytes or immune cells. Instead, protection from HFD‐induced liver injury in Irf3S1/S1 mice was primarily associated with retardation of nuclear translocation of p65 and decreased expression of nuclear factor kappa B (NFκB)‐dependent inflammatory cytokines. Conclusion: Taken together, these data identify important contributions of the nontranscriptional function of IRF3, likely by reducing NFκB signaling, in dampening the hepatic inflammatory environment in response to an HFD.

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Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice

Abstract: Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.

Cited by 286 publications

References 45 publications

Coordinated changes of gut microbiome and lipidome differentiates nonalcoholic steatohepatitis (NASH) from isolated steatosis

Coordinated changes of gut microbiome and lipidome differentiates nonalcoholic steatohepatitis (NASH) from isolated steatosis

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Nontranscriptional Activity of Interferon Regulatory Factor 3 Protects Mice From High‐Fat Diet‐Induced Liver Injury

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