bims-nastce Biomed News
on NASH and T cells
Issue of 2021–08–22
ten papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. E-selectin-dependent inflammation and lipolysis in adipose tissue exacerbate steatosis-to-NASH progression via S100A8/9.
  2. Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity.
  3. Hepatic sexual dimorphism - implications for non-alcoholic fatty liver disease.
  4. Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer.
  5. TIM4+ adipose tissue-resident macrophages: new modulators of adiposity.
  6. Sex- and age-dependent outcomes of 9-hour time-restricted feeding of a Western high-fat high-sucrose diet in C57BL/6J mice.
  7. Corrigendum: Immunological Impact of Intestinal T Cells on Metabolic Diseases.
  8. Roles and Mechanisms of TGR5 in the Modulation of CD4+ T Cell Functions in Myocardial Infarction.
  9. Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation.
  10. Extracellular vesicles from in vivo liver tissue accelerate recovery of liver necrosis induced by carbon tetrachloride.
  1. Cell Mol Gastroenterol Hepatol. 2021 Aug 11. pii: S2352-345X(21)00169-7. [Epub ahead of print]
    E-selectin-dependent inflammation and lipolysis in adipose tissue exacerbate steatosis-to-NASH progression via S100A8/9.
    Robim M Rodrigues, Yong He, Seonghwan Hwang, Adeline Bertola, Bryan Mackowiak, Yeni Ait-Ahmed, Wonhyo Seo, Jing Ma, Xiaolin Wang, Seol Hee Park, Yukun Guan, Yaojie Fu, Tamara Vanhaecke, Dechun Feng, Bin Gao.
       BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH is also associated with adipose tissue (AT) inflammation, but the role of AT inflammation in NASH pathogenesis remains obscure. The aim of this study is to investigate the interplay between neutrophil recruitment in AT and the progression of NASH.
    METHODS: A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus-Cxcl1 overexpression (HFD+AdCxcl1). Genetic deletion E-selectin (Sele) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model.
    RESULTS: By analyzing transcriptomic datasets of AT from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest upregulated gene among neutrophil recruitment-related factors in AT of NASH patients compared to those in patients with simple steatosis. A marked upregulation of Sele in AT was also observed in HFD+AdCxcl1 mice. The HFD+AdCxcl1-induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in AT, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils was highly elevated in AT of HFD+AdCxcl1 mice. This elevation was blunted in the Sele KO mice. Therapeutically, treatment with the S100A inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice.
    CONCLUSIONS: E-selectin plays an important role in inducing neutrophil recruitment in AT, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting AT inflammation may therefore represent a potential novel therapy for treatment of NASH.
    Keywords:  CXCL1; Non-alcoholic fatty liver disease (NAFLD); Paquinimod; neutrophils; steatohepatitis
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.08.002
  2. Nat Metab. 2021 Aug;3(8): 1042-1057
    Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity.
    Benedikt Hild, Matthew S Dreier, Ji Hoon Oh, John A McCulloch, Jonathan H Badger, Juen Guo, Claire E Thefaine, Regina Umarova, Kevin D Hall, Oksana Gavrilova, Stephan P Rosshart, Giorgio Trinchieri, Barbara Rehermann.
      Obesity and its consequences are among the greatest challenges in healthcare. The gut microbiome is recognized as a key factor in the pathogenesis of obesity. Using a mouse model, we show here that a wild-derived microbiome protects against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. This phenotype is transferable only during the first weeks of life. In adult mice, neither transfer nor severe disturbance of the wild-type microbiome modifies the metabolic response to a high-fat diet. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue. Thus, we identify a microbiome that protects against weight gain and its negative consequences through metabolic programming in early life. Translation of these results to humans may identify early-life therapeutics that protect against obesity.
    DOI:  https://doi.org/10.1038/s42255-021-00439-y
  3. Nat Rev Endocrinol. 2021 Aug 20.
    Hepatic sexual dimorphism - implications for non-alcoholic fatty liver disease.
    Philippe Lefebvre, Bart Staels.
      The liver is often thought of as a single functional unit, but both its structural and functional architecture make it highly multivalent and adaptable. In any given physiological situation, the liver can maintain metabolic homeostasis, conduct appropriate inflammatory responses, carry out endobiotic and xenobiotic transformation and synthesis reactions, as well as store and release multiple bioactive molecules. Moreover, the liver is a very resilient organ. This resilience means that chronic liver diseases can go unnoticed for decades, yet culminate in life-threatening clinical complications once the adaptive capacity of the liver is overwhelmed. Non-alcoholic fatty liver disease (NAFLD) predisposes individuals to cirrhosis and increases liver-related and cardiovascular disease-related mortality. This Review discusses the accumulating evidence of sexual dimorphism in NAFLD, which is currently rarely considered in preclinical and clinical studies. Increased awareness of the mechanistic causes of hepatic sexual dimorphism could lead to improved understanding of the biological processes that are dysregulated in NAFLD, to the identification of relevant therapeutic targets and to improved risk stratification of patients with NAFLD undergoing therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41574-021-00538-6
  4. Cell. 2021 Aug 13. pii: S0092-8674(21)00888-6. [Epub ahead of print]
    Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer.
    JRI Live Cell Bank
      Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.
    Keywords:  checkpoint blockade immunotherapy; colorectal cancer; innate lymphoid cells; intestinal inflammation; microbiota
    DOI:  https://doi.org/10.1016/j.cell.2021.07.029
  5. Nat Rev Endocrinol. 2021 Aug 19.
    TIM4+ adipose tissue-resident macrophages: new modulators of adiposity.
    Jin Young Huh, Jae Bum Kim.
      
    DOI:  https://doi.org/10.1038/s41574-021-00554-6
  6. Cell Rep. 2021 Aug 17. pii: S2211-1247(21)00977-3. [Epub ahead of print]36(7): 109543
    Sex- and age-dependent outcomes of 9-hour time-restricted feeding of a Western high-fat high-sucrose diet in C57BL/6J mice.
    Amandine Chaix, Shaunak Deota, Raghav Bhardwaj, Terry Lin, Satchidananda Panda.
      Time-restricted feeding (TRF) is a nutritional intervention wherein food intake is limited to a consistent 8- to 10-h daily window without changes in nutritional quality or quantity. TRF can prevent and treat diet-induced obesity (DIO) and associated metabolic disease in young male mice fed an obesogenic diet, the gold standard preclinical model for metabolic disease research. Because age and sex are key biological variables affecting metabolic disease pathophysiology and response to therapies, we assessed their impact on TRF benefits by subjecting young 3-month-old or middle-aged 12-month-old male and female mice to ad libitum or TRF of a Western diet. We show that most of the benefits of TRF are age-independent but are sex-dependent. TRF protects both sexes against fatty liver and glucose intolerance while body weight benefits are observed only in males. We also find that TRF imparts performance benefits and increases survival to sepsis in both sexes.
    Keywords:  aging; circadian rhythms; diet-induced obesity; endurance; fatty liver; motor coordination; sepsis; sex differences; time-restricted feeding; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.celrep.2021.109543
  7. Front Immunol. 2021 ;12 682376
    Corrigendum: Immunological Impact of Intestinal T Cells on Metabolic Diseases.
    Haiyan Zhou, Liwen Wang, Feng Liu.
      [This corrects the article DOI: 10.3389/fimmu.2021.639902.].
    Keywords:  T cells; dietary signals; intestine; microbiota; obesity
    DOI:  https://doi.org/10.3389/fimmu.2021.682376
  8. J Cardiovasc Transl Res. 2021 Aug 16.
    Roles and Mechanisms of TGR5 in the Modulation of CD4+ T Cell Functions in Myocardial Infarction.
    Jiaxing Wang, Tan Xu, Ming Xu.
      Bile acid receptor TGR5 has been proved to play protective roles in the process of myocardial infarction (MI). Recently, we found spleen weight of Tgr5+/+ mice was increased at 7-day post-MI but not in Tgr5-/- mice. Since the spleen is one of the main resources of immune and inflammatory cells post-MI, we conducted flow cytometry analysis of multiple immune cells in the heart post-MI. It showed the recruitment of CD4+ T cells and CD8+ T cells was continuously more in the heart of Tgr5-/- mice post-MI until 7 days after MI. Furthermore, CD4-specific TGR5 depletion mice exhibited aggravated ischemic injury. The mRNA expressions of the markers of Th1 and Treg were upregulated in the heart of Tgr5-/- mice at 7-day post-MI. These results suggested TGR5 modulates CD4+ T cell functions and subsets distribution in the heart, and plays protective roles in myocardial infarction.
    Keywords:  Immunomodulation; Myocardial infarction; T cell; TGR5
    DOI:  https://doi.org/10.1007/s12265-021-10164-2
  9. Proc Natl Acad Sci U S A. 2021 Aug 24. pii: e2025813118. [Epub ahead of print]118(34):
    Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation.
    Catherine Larochelle, Beatrice Wasser, Hélène Jamann, Julian T Löffel, Qiao-Ling Cui, Olivier Tastet, Miriam Schillner, Dirk Luchtman, Jérôme Birkenstock, Albrecht Stroh, Jack Antel, Stefan Bittner, Frauke Zipp.
      T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.
    Keywords:  CD29 blockade; Th17 cells; glutamate; intravital microscopy; oligodendrocytes
    DOI:  https://doi.org/10.1073/pnas.2025813118
  10. J Extracell Vesicles. 2021 Aug;10(10): e12133
    Extracellular vesicles from in vivo liver tissue accelerate recovery of liver necrosis induced by carbon tetrachloride.
    Jaemin Lee, Sae Rom Kim, Changjin Lee, Ye In Jun, Seoyoon Bae, Yae Jin Yoon, Oh Youn Kim, Yong Song Gho.
      Extracellular vesicles (EVs) are nano-sized vesicles composed of proteolipid bilayers carrying various molecular signatures of the cells. As mediators of intercellular communications, EVs have gained great attention as new therapeutic agents in the field of nanomedicine. Therefore, many studies have explored the roles of cell-derived EVs isolated from cultured hepatocytes or stem cells as inducer of liver proliferation and regeneration under various pathological circumstances. However, study investigating the role of EVs directly isolated from liver tissue has not been performed. Herein, to understand the pathophysiological role and to investigate the therapeutic potential of in vivo liver EVs, we isolated EVs from both normal and carbon tetrachloride (CCl4)-induced damaged in vivo liver tissues. The in vivo EVs purified from liver tissues display typical features of EVs including spherical morphology, nano-size, and enrichment of tetraspanins. Interestingly, administration of both normal and damaged liver EVs significantly accelerated the recovery of liver tissue from CCl4-induced hepatic necrosis. This restorative action was through the induction of hepatocyte growth factor at the site of the injury. These results suggest that not only normal liver EVs but also damaged liver EVs play important pathophysiological roles of maintaining homeostasis after tissue damage. Our study, therefore, provides new insight into potentially developing in vivo EV-based therapeutics for preventing and treating liver diseases.
    Keywords:  extracellular vesicles; hepatocyte growth factor; isolation; liver failure; therapeutics; tissue engineering
    DOI:  https://doi.org/10.1002/jev2.12133
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