bims-nastce Biomed News
on NASH and T cells
Issue of 2021–08–29
eleven papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Immunonano-Lipocarrier-Mediated Liver Sinusoidal Endothelial Cell-Specific RUNX1 Inhibition Impedes Immune Cell Infiltration and Hepatic Inflammation in Murine Model of NASH.
  2. Immunomodulatory Effects of Canine Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles on Stimulated CD4+ T Cells Isolated from Peripheral Blood Mononuclear Cells.
  3. Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells.
  4. Cyp2c-deficiency depletes muricholic acids and protects against high fat diet-induced obesity in male mice but promotes liver damage.
  5. Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease.
  6. Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes.
  7. Dietary fructose acts on gut to increase nutrient uptake.
  8. Innate control of adaptive immunity and adaptive instruction of innate immunity: bi-directional flow of information.
  9. The Other Side of Malnutrition in Inflammatory Bowel Disease (IBD): Non-Alcoholic Fatty Liver Disease.
  10. First we eat, then we do everything else: The dynamic metabolic regulation of efferocytosis.
  11. Circ_0057558 promotes nonalcoholic fatty liver disease by regulating ROCK1/AMPK signaling through targeting miR-206.
  1. Int J Mol Sci. 2021 Aug 06. pii: 8489. [Epub ahead of print]22(16):
    Immunonano-Lipocarrier-Mediated Liver Sinusoidal Endothelial Cell-Specific RUNX1 Inhibition Impedes Immune Cell Infiltration and Hepatic Inflammation in Murine Model of NASH.
    Dinesh Mani Tripathi, Sumati Rohilla, Impreet Kaur, Hamda Siddiqui, Preety Rawal, Pinky Juneja, Vikash Kumar, Anupama Kumari, Vegi Ganga Modi Naidu, Seeram Ramakrishna, Subham Banerjee, Rekha Puria, Shiv K Sarin, Savneet Kaur.
       BACKGROUND: Runt-related transcription factor (RUNX1) regulates inflammation in non-alcoholic steatohepatitis (NASH).
    METHODS: We performed in vivo targeted silencing of the RUNX1 gene in liver sinusoidal endothelial cells (LSECs) by using vegfr3 antibody tagged immunonano-lipocarriers encapsulated RUNX1 siRNA (RUNX1 siRNA) in murine models of methionine choline deficient (MCD) diet-induced NASH. MCD mice given nanolipocarriers-encapsulated negative siRNA were vehicle, and mice with standard diet were controls.
    RESULTS: Liver RUNX1 expression was increased in the LSECs of MCD mice in comparison to controls. RUNX1 protein expression was decreased by 40% in CD31-positive LSECs of RUNX1 siRNA mice in comparison to vehicle, resulting in the downregulation of adhesion molecules, ICAM1 expression, and VCAM1 expression in LSECs. There was a marked decrease in infiltrated T cells and myeloid cells along with reduced inflammatory cytokines in the liver of RUNX1 siRNA mice as compared to that observed in the vehicle.
    CONCLUSIONS: In vivo LSEC-specific silencing of RUNX1 using immunonano-lipocarriers encapsulated siRNA effectively reduces its expression of adhesion molecules, infiltrate on of immune cells in liver, and inflammation in NASH.
    Keywords:  immunonano-lipocarriers; inflammation; liver sinusoidal endothelial cells; non-alcoholic steatohepatitis; targeted delivery
    DOI:  https://doi.org/10.3390/ijms22168489
  2. J Immunol Res. 2021 ;2021 2993043
    Immunomodulatory Effects of Canine Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles on Stimulated CD4+ T Cells Isolated from Peripheral Blood Mononuclear Cells.
    Takahiro Teshima, Yunosuke Yuchi, Ryohei Suzuki, Hirotaka Matsumoto, Hidekazu Koyama.
      Adipose tissue-derived mesenchymal stem cells (ADSCs) have anti-inflammatory and immunomodulatory characteristics. Many studies have suggested that the immunomodulation of ADSCs is largely mediated by secreted paracrine factors. Various factors are secreted from ADSCs, among which extracellular vesicles are considered to play a major role in the communication between ADSCs and target cells. Several studies have reported the function of canine ADSC-derived extracellular vesicles (cADSC-EVs), but few studies have reported the immunomodulatory effects of cADSC-EVs on immune cells. The purpose of this study was to investigate the effects of cADSC-EVs on in vitro-stimulated CD4+ T cells isolated from peripheral blood mononuclear cells (PBMCs). cADSC-EVs were isolated from cADSCs under naive conditions or primed conditions by tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ). The expression levels of several microRNAs in cADSC-EVs were altered by priming with TNFα and IFNγ. Culturing PBMCs stimulated with concanavalin A in the presence of naive or primed cADSC-EVs inhibited the differentiation of PBMCs and CD4+ T cells and promoted apoptosis of PBMCs. CD4+, CD8+, and CD4+CD8+ T cells were decreased, while CD3+CD4-CD8- T cells were increased. T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells were analyzed by flow cytometry. cADSC-EVs inhibited the proliferation of Th1 and Th17 cells and enhanced Th2 and Treg cell proliferation. However, CD4+ T cells that had incorporated labeled cADSC-EVs comprised only a few percent of all cells. Therefore, these responses of stimulated CD4+ T cells may be due to not only direct effects of cADSC-EVs but also to indirect effects through interactions between cADSC-EVs and other immune cells. In conclusion, cADSC-EVs exert immunosuppressive effects on stimulated CD4+ T cells in vitro. These findings may be useful for further studies of immune diseases.
    DOI:  https://doi.org/10.1155/2021/2993043
  3. Front Immunol. 2021 ;12 728783
    Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells.
    Jingli Lu, Yan Liang, Haiyang Meng, Ailing Zhang, Junjie Zhao, Chengliang Zhang.
      Forkhead box protein 3 (Foxp3+)-expressing regulatory T (Treg) cells are a unique CD4+T cell subset that suppresses excessive immune responses. The epigenetic plasticity and metabolic traits of Treg cells are crucial for the acquisition of their phenotypic and functional characteristics. Therefore, alterations to the epigenetics and metabolism affect Treg cell development and function. Recent evidence reveals that altering the metabolic pathways and generation of metabolites can regulate the epigenetics of Treg cells. Specifically, some intermediates of cell metabolism can directly act as substrates or cofactors of epigenetic-modifying enzymes. Here, we describe the metabolic and epigenetic features during Treg cell development, and discuss how metabolites can contribute to epigenetic alterations of Treg cells, which affects Treg cell activation, differentiation, and function.
    Keywords:  epigenetics; immune suppression; metabolism; metabolites; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2021.728783
  4. Mol Metab. 2021 Aug 23. pii: S2212-8778(21)00173-3. [Epub ahead of print] 101326
    Cyp2c-deficiency depletes muricholic acids and protects against high fat diet-induced obesity in male mice but promotes liver damage.
    Antwi-Boasiako Oteng, Sei Higuchi, Alexander S Banks, Rebecca A Haeusler.
       OBJECTIVE: Murine-specific muricholic acids (MCAs) are reported to protect against obesity and associated metabolic disorders. However, the response of mice with genetic depletion of MCA to an obesogenic diet has not been evaluated. We used Cyp2c-deficient (Cyp2c-/-) mice, which lack MCAs and thus have a human-like bile acid (BA) profile, to directly investigate the potential role of MCAs in diet-induced obesity.
    METHODS: Male and female Cyp2c-/- mice and wild-type littermate controls were fed a standard chow diet or a high fat diet (HFD) for 18 weeks. We measured BA composition from a pool of liver, gallbladder, and intestine, as well as weekly body weight, food intake, lean and fat mass, systemic glucose homeostasis, energy expenditure, intestinal lipid absorption, fecal lipid, and energy content.
    RESULTS: Cyp2c deficiency depleted MCAs and caused other changes in BA composition, namely a decrease in the ratio of 12α-hydroxylated (12α-OH) BAs to non-12α-OH BAs, without altering the total BA levels. While wild-type male mice became obese after HFD-feeding, Cyp2c-/- male mice were protected from obesity and associated metabolic dysfunctions. Cyp2c-/- male mice also showed reduced intestinal lipid absorption and increased lipid excretion, which was reversed by oral gavage with the 12α-OH BA, taurocholic acid. Cyp2c-/- mice also showed increased liver damage, which appeared stronger in females.
    CONCLUSION: MCA does not protect against diet-induced obesity but may protect against liver injury. Reduced lipid absorption in Cyp2c-deficient male mice is potentially due to a reduced ratio of 12α-OH/non-12α-OH BAs.
    Keywords:  Bile acid; Lipid absorption; glucose homeostasis; liver fibrosis; muricholic acid; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2021.101326
  5. Cells. 2021 Aug 12. pii: 2072. [Epub ahead of print]10(8):
    Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease.
    Tianhao Zhou, Debjyoti Kundu, Jonathan Robles-Linares, Vik Meadows, Keisaku Sato, Leonardo Baiocchi, Burcin Ekser, Shannon Glaser, Gianfranco Alpini, Heather Francis, Lindsey Kennedy.
      Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.
    Keywords:  bile acids; cholangiocytes; cholestatic liver disease; ductular reaction; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/cells10082072
  6. Cell Rep. 2021 Aug 24. pii: S2211-1247(21)01046-9. [Epub ahead of print]36(8): 109608
    Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes.
    Teruyuki Sano, Takahiro Kageyama, Victoria Fang, Ranit Kedmi, Carlos Serafin Martinez, Jhimmy Talbot, Alessandra Chen, Ivan Cabrera, Oleksandra Gorshko, Reina Kurakake, Yi Yang, Charles Ng, Susan R Schwab, Dan R Littman.
      Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria.
    Keywords:  CD4 T cells; IL-17A; Peyer’s patches; T cell activation; cytokine receptors; homeostatic Th17 cells; ileum; lymphocyte homing; mucosal immunology; nuclear receptors
    DOI:  https://doi.org/10.1016/j.celrep.2021.109608
  7. Nat Rev Endocrinol. 2021 Aug 27.
    Dietary fructose acts on gut to increase nutrient uptake.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-021-00561-7
  8. Curr Opin Immunol. 2021 Aug 20. pii: S0952-7915(21)00106-0. [Epub ahead of print]73 25-33
    Innate control of adaptive immunity and adaptive instruction of innate immunity: bi-directional flow of information.
    Margaret M McDaniel, Hannah E Meibers, Chandrashekhar Pasare.
      The ability of the innate and adaptive immune systems to communicate with each other is central to protective immune responses and maintenance of host health. Myeloid cells of the innate immune system are able to sense microbial ligands, perturbations in cellular homeostasis, and virulence factors, thereby allowing them to relay distinct pathogen-specific information to naïve T cells in the form of pathogen-derived peptides and a unique cytokine milieu. Once primed, effector T helper cells produce lineage-defining cytokines to help combat the original pathogen, and a subset of these cells persist as memory or effector-memory populations. These memory T cells then play a dual role in host protection by not only responding rapidly to reinfection, but by also directly instructing myeloid cells to express licensing cytokines. This means there is a bi-directional flow of information first from the innate to the adaptive immune system, and then from the adaptive back to innate immune system. Here, we focus on how signals, first from pathogens and then from primed effector and memory T cells, are integrated by myeloid cells and its consequences for protective immunity or systemic inflammation.
    DOI:  https://doi.org/10.1016/j.coi.2021.07.013
  9. Nutrients. 2021 Aug 13. pii: 2772. [Epub ahead of print]13(8):
    The Other Side of Malnutrition in Inflammatory Bowel Disease (IBD): Non-Alcoholic Fatty Liver Disease.
    Giulia Gibiino, Alessandro Sartini, Stefano Gitto, Cecilia Binda, Monica Sbrancia, Chiara Coluccio, Vittorio Sambri, Carlo Fabbri.
      Steatohepatitis and hepatobiliary manifestations constitute some of the most common extra-intestinal manifestations of Inflammatory Bowel Disease (IBD). On the other hand, non-alcoholic fatty liver disease (NAFLD) affects around 25% of the world's population and is attracting ever more attention in liver transplant programs. To outline the specific pathways linking these two conditions is a pressing task for 21st-century researchers. We are accustomed to expecting the occurrence of fatty liver disease in obese people, but current evidence suggests that there are several different pathways also occurring in underweight patients. Genetic factors, inflammatory signals and microbiota are key players that could help in understanding the entire pathogenesis of NAFLD, with the aim of defining the multiple expressions of malnutrition. In the current review, we summarize the most recent literature regarding the epidemiology, pathogenesis and future directions for the management of NAFLD in patients affected by IBD.
    Keywords:  leaky gut; metabolic syndrome; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.3390/nu13082772
  10. Cell Metab. 2021 Aug 17. pii: S1550-4131(21)00364-8. [Epub ahead of print]
    First we eat, then we do everything else: The dynamic metabolic regulation of efferocytosis.
    Alissa Trzeciak, Ya-Ting Wang, Justin Shaun Arnold Perry.
      Clearance of apoptotic cells, or "efferocytosis," is essential for diverse processes including embryonic development, tissue turnover, organ regeneration, and immune cell development. The human body is estimated to remove approximately 1% of its body mass via apoptotic cell clearance daily. This poses several intriguing cell metabolism problems. For instance, phagocytes such as macrophages must induce or suppress metabolic pathways to find, engulf, and digest apoptotic cells. Then, phagocytes must manage the potentially burdensome biomass of the engulfed apoptotic cell. Finally, phagocytes reside in complex tissue architectures that vary in nutrient availability, the types of dying cells or debris that require clearance, and the neighboring cells they interact with. Here, we review advances in our understanding of these three key areas of phagocyte metabolism. We end by proposing a model of efferocytosis that integrates recent findings and establishes a new paradigm for testing how efferocytosis prevents chronic inflammatory disease and autoimmunity.
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.001
  11. Cell Death Dis. 2021 Aug 26. 12(9): 809
    Circ_0057558 promotes nonalcoholic fatty liver disease by regulating ROCK1/AMPK signaling through targeting miR-206.
    Xi Chen, Qing-Qing Tan, Xin-Rui Tan, Shi-Jun Li, Xing-Xing Zhang.
      Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver disorders that is featured by the extensive deposition of fat in the hepatocytes. Current treatments are very limited due to its unclear pathogenesis. Here, we investigated the function of circ_0057558 and miR-206 in NAFLD. High-fat diet (HFD) feeding mouse was used as an in vivo NAFLD model and long-chain-free fatty acid (FFA)-treated liver cells were used as an in vitro NAFLD model. qRT-PCR was used to measure levels of miR-206, ROCK1 mRNA, and circ_0057558, while Western blotting was employed to determine protein levels of ROCK1, p-AMPK, AMPK, and lipogenesis-related proteins. Immunohistochemistry were performed to examine ROCK1 level. Oil-Red O staining was used to assess the lipid deposition in cells. ELISA was performed to examine secreted triglyceride (TG) level. Dual-luciferase assay was used to validate interactions of miR-206/ROCK1 and circ_0057558/miR-206. RNA immunoprecipitation was employed to confirm the binding of circ_0057558 with miR-206. Circ_0057558 was elevated while miR-206 was reduced in both in vivo and in vitro NAFLD models. miR-206 directly bound with ROCK1 3'-UTR and suppressed lipogenesis and TG secretion through targeting ROCK1/AMPK signaling. Circ_0057558 directly interacted with miR-206 to disinhibit ROCK1/AMPK signaling. Knockdown of circ_0057558 or overexpression of miR-206 inhibited lipogenesis, TG secretion and expression of lipogenesis-related proteins. ROCK1 knockdown reversed the effects of circ_0057558 overexpression. Injection of miR-206 mimics significantly ameliorated NAFLD progression in vivo. Circ_0057558 acts as a miR-206 sponge to de-repress the ROCK1/AMPK signaling and facilitates lipogenesis and TG secretion, which greatly contributes to NAFLD development and progression.
    DOI:  https://doi.org/10.1038/s41419-021-04090-z
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