bims-nastce Biomed News
on NASH and T cells
Issue of 2021–10–03
twelve papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Crosstalk between Metabolic Disorders and Immune Cells.
  2. Inflammatory and fibrotic mechanisms in NAFLD-Implications for new treatment strategies.
  3. Liver Zonation - Revisiting Old Questions With New Technologies.
  4. Low brown adipose tissue activity linked to NAFLD.
  5. Mapping the human gut.
  6. Adipose Tissue Immunometabolism and Apoptotic Cell Clearance.
  7. Cognate recognition of microbial antigens defines constricted CD4+ T cell receptor repertoires in the inflamed colon.
  8. Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis.
  9. Systematic investigation of cytokine signaling activity at the tissue and single-cell levels.
  10. Functional and metabolic fitness of human CD4+ T lymphocytes during metabolic stress.
  11. Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity.
  12. Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis.
  1. Int J Mol Sci. 2021 Sep 16. pii: 10017. [Epub ahead of print]22(18):
    Crosstalk between Metabolic Disorders and Immune Cells.
    Shinichi Saitoh, Koen Van Wijk, Osamu Nakajima.
      Metabolic syndrome results from multiple risk factors that arise from insulin resistance induced by abnormal fat deposition. Chronic inflammation owing to obesity primarily results from the recruitment of pro-inflammatory M1 macrophages into the adipose tissue stroma, as the adipocytes within become hypertrophied. During obesity-induced inflammation in adipose tissue, pro-inflammatory cytokines are produced by macrophages and recruit further pro-inflammatory immune cells into the adipose tissue to boost the immune response. Here, we provide an overview of the biology of macrophages in adipose tissue and the relationship between other immune cells, such as CD4+ T cells, natural killer cells, and innate lymphoid cells, and obesity and type 2 diabetes. Finally, we discuss the link between the human pathology and immune response and metabolism and further highlight potential therapeutic targets for the treatment of metabolic disorders.
    Keywords:  5-aminolevulinic acid; CD4+ T cells; M1/M2 macrophages; chronic inflammation; cytokine; innate lymphoid cells; mesenchymal stem cells; natural killer cells; non-obese metabolic disorder; obesity
    DOI:  https://doi.org/10.3390/ijms221810017
  2. J Intern Med. 2021 Sep 26.
    Inflammatory and fibrotic mechanisms in NAFLD-Implications for new treatment strategies.
    Youngmin A Lee, Scott L Friedman.
      Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.
    Keywords:  fibrosis; insulin resistance; lipotoxicity; liver cancer; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1111/joim.13380
  3. Front Physiol. 2021 ;12 732929
    Liver Zonation - Revisiting Old Questions With New Technologies.
    Rory P Cunningham, Natalie Porat-Shliom.
      Despite the ever-increasing prevalence of non-alcoholic fatty liver disease (NAFLD), the etiology and pathogenesis remain poorly understood. This is due, in part, to the liver's complex physiology and architecture. The liver maintains glucose and lipid homeostasis by coordinating numerous metabolic processes with great efficiency. This is made possible by the spatial compartmentalization of metabolic pathways a phenomenon known as liver zonation. Despite the importance of zonation to normal liver function, it is unresolved if and how perturbations to liver zonation can drive hepatic pathophysiology and NAFLD development. While hepatocyte heterogeneity has been identified over a century ago, its examination had been severely hindered due to technological limitations. Recent advances in single cell analysis and imaging technologies now permit further characterization of cells across the liver lobule. This review summarizes the advances in examining liver zonation and elucidating its regulatory role in liver physiology and pathology. Understanding the spatial organization of metabolism is vital to further our knowledge of liver disease and to provide targeted therapeutic avenues.
    Keywords:  architecture; liver; physiology; technologies; zonation
    DOI:  https://doi.org/10.3389/fphys.2021.732929
  4. Nat Rev Endocrinol. 2021 Sep 30.
    Low brown adipose tissue activity linked to NAFLD.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-021-00579-x
  5. Nat Rev Gastroenterol Hepatol. 2021 Sep 28.
    Mapping the human gut.
    Jordan Hindson.
      
    DOI:  https://doi.org/10.1038/s41575-021-00530-5
  6. Cells. 2021 Sep 02. pii: 2288. [Epub ahead of print]10(9):
    Adipose Tissue Immunometabolism and Apoptotic Cell Clearance.
    Tamás Röszer.
      The safe removal of apoptotic debris by macrophages-often referred to as efferocytosis-is crucial for maintaining tissue integrity and preventing self-immunity or tissue damaging inflammation. Macrophages clear tissues of hazardous materials from dying cells and ultimately adopt a pro-resolving activation state. However, adipocyte apoptosis is an inflammation-generating process, and the removal of apoptotic adipocytes by so-called adipose tissue macrophages triggers a sequence of events that lead to meta-inflammation and obesity-associated metabolic diseases. Signals that allow apoptotic cells to control macrophage immune functions are complex and involve metabolites released by the apoptotic cells and also metabolites produced by the macrophages during the digestion of apoptotic cell contents. This review provides a concise summary of the adipocyte-derived metabolites that potentially control adipose tissue macrophage immune functions and, hence, may induce or alleviate adipose tissue inflammation.
    Keywords:  M2 macrophage; apoptosis; efferocytosis; immunometabolism; macrophage; meta-inflammation; obesity; phagocytosis
    DOI:  https://doi.org/10.3390/cells10092288
  7. Immunity. 2021 Sep 23. pii: S1074-7613(21)00346-0. [Epub ahead of print]
    Cognate recognition of microbial antigens defines constricted CD4+ T cell receptor repertoires in the inflamed colon.
    Moritz Muschaweck, Lydia Kopplin, Fabio Ticconi, Angela Schippers, Aida Iljazovic, Eric J C Gálvez, Ali T Abdallah, Norbert Wagner, Ivan G Costa, Till Strowig, Oliver Pabst.
      Key aspects of intestinal T cells, including their antigen specificity and their selection by the microbiota and other intestinal antigens, as well as the contribution of individual T cell clones to regulatory and effector functions, remain unresolved. Here we tracked adoptively transferred T cell populations to specify the interrelation of T cell receptor repertoire and the gut antigenic environment. We show that dominant TCRα clonotypes were shared between interferon-γ- and interleukin-17-producing but not regulatory Foxp3+ T cells. Identical TCRα clonotypes accumulated in the colon of different individuals, whereas antibiotics or defined colonization correlated with the expansion of distinct expanded T cell clonotypes. Our results demonstrate key aspects of intestinal CD4+ T cell activation and suggest that few microbial species exert a dominant effect on the intestinal T cell repertoire during colitis. We speculate that dominant proinflammatory T cell clones might provide a therapeutic target in human inflammatory bowel disease.
    Keywords:  colitis, CD4+ T cells, T cell receptor repertoire, microbiota, regulatory T cells
    DOI:  https://doi.org/10.1016/j.immuni.2021.08.014
  8. Sci Rep. 2021 Sep 29. 11(1): 19396
    Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis.
    Zhong-Yi Wang, Adrian Keogh, Annick Waldt, Rachel Cuttat, Marilisa Neri, Shanshan Zhu, Sven Schuierer, Alexandra Ruchti, Christophe Crochemore, Judith Knehr, Julie Bastien, Iwona Ksiazek, Daniel Sánchez-Taltavull, Hui Ge, Jing Wu, Guglielmo Roma, Stephen B Helliwell, Deborah Stroka, Florian Nigsch.
      Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding of this disease is limited by an incomplete characterization of liver cell types in general and hepatic stellate cells (HSCs) in particular, given that activated HSCs are the major hepatic fibrogenic cell population. To help fill this gap, we profiled 17,810 non-parenchymal cells derived from six healthy human livers. In conjunction with public single-cell data of fibrotic/cirrhotic human livers, these profiles enable the identification of potential intercellular signaling axes (e.g., ITGAV-LAMC1, TNFRSF11B-VWF and NOTCH2-DLL4) and master regulators (e.g., RUNX1 and CREB3L1) responsible for the activation of HSCs during fibrogenesis. Bulk RNA-seq data of NASH patient livers and rodent models for liver fibrosis of diverse etiologies allowed us to evaluate the translatability of candidate therapeutic targets for NASH-related fibrosis. We identified 61 liver fibrosis-associated genes (e.g., AEBP1, PRRX1 and LARP6) that may serve as a repertoire of translatable drug target candidates. Consistent with the above regulon results, gene regulatory network analysis allowed the identification of CREB3L1 as a master regulator of many of the 61 genes. Together, this study highlights potential cell-cell interactions and master regulators that underlie HSC activation and reveals genes that may represent prospective hallmark signatures for liver fibrosis.
    DOI:  https://doi.org/10.1038/s41598-021-98806-y
  9. Nat Methods. 2021 Sep 30.
    Systematic investigation of cytokine signaling activity at the tissue and single-cell levels.
    Peng Jiang, Yu Zhang, Beibei Ru, Yuan Yang, Trang Vu, Rohit Paul, Amer Mirza, Grégoire Altan-Bonnet, Lingrui Liu, Eytan Ruppin, Lalage Wakefield, Kai W Wucherpfennig.
      Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig; https://cytosig.ccr.cancer.gov/ ), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.
    DOI:  https://doi.org/10.1038/s41592-021-01274-5
  10. Life Sci Alliance. 2021 Dec;pii: e202101013. [Epub ahead of print]4(12):
    Functional and metabolic fitness of human CD4+ T lymphocytes during metabolic stress.
    Lisa Holthaus, Virag Sharma, Daniel Brandt, Anette-Gabriele Ziegler, Martin Jastroch, Ezio Bonifacio.
      Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T-cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, whereas early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T-cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T-cell proliferation, but not T-cell activation. Conditions that inhibited T-cell activation were associated with the down-regulation of 2',5'-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T-cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress, and/or the function of T cells in these conditions will improve the efficacy of T-cell-based therapies.
    DOI:  https://doi.org/10.26508/lsa.202101013
  11. World J Gastroenterol. 2021 Sep 07. 27(33): 5555-5565
    Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity.
    Yan-Xia Wei, Kui-Yang Zheng, Yu-Gang Wang.
      A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant "map'' of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.
    Keywords:  Gut; Metabolic diseases; Microbial metabolites; Microbiota; Mucosal homeostasis; Obesity
    DOI:  https://doi.org/10.3748/wjg.v27.i33.5555
  12. J Lipid Res. 2021 Sep 23. pii: S0022-2275(21)00105-X. [Epub ahead of print] 100123
    Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis.
    Yan Xie, Elizabeth P Newberry, Elizabeth M Brunt, Samuel J Ballentine, Saeed Soleymanjahi, Elizabeth A Molitor, Nicholas O Davidson.
      Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline deficient (MCD) diet exhibited reduced hepatic triglycerides (TG), inflammation and fibrosis, associated with reduced oxidative stress and downstream activation of JNK and NFκB signaling pathways. However, when Mttpflox mice were fed a MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced but inflammation and fibrosis were increased after 10 days reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks MCD feeding, to 30 days led to sustained reductions in hepatic TG but neither inflammation nor fibrosis were decreased and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high fat/fructose/cholesterol diet for 10weeks, then switched to chow ± tamoxifen (HFFC→chow) or (HFFC→ Mttp-IKO chow), but again neither inflammation or fibrosis were affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50-90 fold reductions in hepatic TG.
    Keywords:  Intestine; antioxidant; apolipoproteinB; fibrosis; hepatic lipogenesis; intestinal permeability; lipid absorption; lipoproteins; microsomal triglyceride transfer protein; oxidative stress
    DOI:  https://doi.org/10.1016/j.jlr.2021.100123
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