bims-nastce Biomed News
on NASH and T cells
Issue of 2022–02–20
eight papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells.
  2. IL-17 Receptor C Signaling Controls CD4+ TH17 Immune Responses and Tissue Injury in Immune-Mediated Kidney Diseases.
  3. Liver Zonation, Revisited.
  4. Current approach to hepatobiliary manifestations in inflammatory bowel disease.
  5. FGF4 protects the liver from non-alcoholic fatty liver disease by activating the AMPK-Caspase 6 signal axis.
  6. A robust gene expression signature for NASH in liver expression data.
  7. CCR6 and CXCR6 Identify the Th17 Cells With Cytotoxicity in Experimental Autoimmune Encephalomyelitis.
  8. Analysis and Visualization of Spatial Transcriptomic Data.
  1. Cell Rep. 2022 02 15. pii: S2211-1247(22)00110-3. [Epub ahead of print]38(7): 110389
    IL-6-induced FOXO1 activity determines the dynamics of metabolism in CD8 T cells cross-primed by liver sinusoidal endothelial cells.
    Michael Dudek, Kerstin Lohr, Sainitin Donakonda, Tobias Baumann, Max Lüdemann, Silke Hegenbarth, Lena Dübbel, Carola Eberhagen, Savvoula Michailidou, Abdallah Yassin, Marco Prinz, Bastian Popper, Stefan Rose-John, Hans Zischka, Percy A Knolle.
      Liver sinusoidal endothelial cells (LSECs) are liver-resident antigen (cross)-presenting cells that generate memory CD8 T cells, but metabolic properties of LSECs and LSEC-primed CD8 T cells remain understudied. Here, we report that high-level mitochondrial respiration and constitutive low-level glycolysis support LSEC scavenger and sentinel functions. LSECs fail to increase glycolysis and co-stimulation after TLR4 activation, indicating absence of metabolic and functional maturation compared with immunogenic dendritic cells. LSEC-primed CD8 T cells show a transient burst of oxidative phosphorylation and glycolysis. Mechanistically, co-stimulatory IL-6 signaling ensures high FOXO1 expression in LSEC-primed CD8 T cells, curtails metabolic activity associated with T cell activation, and is indispensable for T cell functionality after re-activation. Thus, distinct immunometabolic features characterize non-immunogenic LSECs compared with immunogenic dendritic cells and LSEC-primed CD8 T cells with memory features compared with effector CD8 T cells. This reveals local features of metabolism and function of T cells in the liver.
    Keywords:  glycolysis; immune cell metabolism; liver immune tolerance; memory T cells; mitochondrial respiration; non-professional antigen-presenting cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.110389
  2. J Am Soc Nephrol. 2021 Dec;32(12): 3081-3098
    IL-17 Receptor C Signaling Controls CD4+ TH17 Immune Responses and Tissue Injury in Immune-Mediated Kidney Diseases.
    Tilman Schmidt, Jonas Luebbe, Christoph Kilian, Jan-Hendrik Riedel, Sonja Hiekmann, Nariaki Asada, Pauline Ginsberg, Lennart Robben, Ning Song, Anna Kaffke, Anett Peters, Alina Borchers, Richard A Flavell, Nicola Gagliani, Penelope Pelzcar, Samuel Huber, Tobias B Huber, Jan-Eric Turner, Hans-Joachim Paust, Christian F Krebs, Ulf Panzer.
       BACKGROUND: IL-17A-producing CD4+ T helper (TH17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD4+ T cell subsets, remains to be elucidated.
    METHODS: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4+ T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated TH17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in TH17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4+CD45RBhigh T cell transfer colitis model.
    RESULTS: We identified a specific expression of the IL-17 receptor A/C complex on CD4+ TH17 cells. Single-cell RNA sequencing of TH17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4+ T cells and, most importantly, specifically in CD4+ TH17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis.
    CONCLUSIONS: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4+ TH17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-TH17 treatment strategies.
    Keywords:  cytokines; glomerulonephritis; immunology; lymphocytes
    DOI:  https://doi.org/10.1681/ASN.2021030426
  3. Hepatology. 2022 Feb 17.
    Liver Zonation, Revisited.
    Jasmin Paris, Neil C Henderson.
      The concept of hepatocyte functional zonation is well established, with differences in metabolism and xenobiotic processing determined by multiple factors including oxygen and nutrient levels across the hepatic lobule. However, recent advances in single cell genomics technologies, including single cell and nuclei RNA sequencing, and the rapidly evolving fields of spatial transcriptomic and proteomic profiling have greatly increased our understanding of liver zonation. Here we discuss how these transformative experimental strategies are being leveraged to dissect liver zonation at unprecedented resolution, and how this new information should facilitate the emergence of novel precision medicine-based therapies for patients with liver disease.
    DOI:  https://doi.org/10.1002/hep.32408
  4. J Physiol Pharmacol. 2021 Oct;72(5):
    Current approach to hepatobiliary manifestations in inflammatory bowel disease.
    K Majchrzak, P Dudek, R Talar-Wojnarowska, J Fichna.
      Inflammatory bowel disease (IBD), including the two main subtypes - Crohn's disease (CD) and ulcerative colitis (UC) - has a wide range of extra-intestinal manifestations (EIMs) that are major causes of morbidity and disability. The following EIMs can be classified as IBD-associated: mucocutaneous, ocular, pulmonary, renal, genitourinary, hematological, neurological, psychiatric, cardiac and hepatobiliary. The latter include primary sclerosing cholangitis (PSC), cholelithiasis, IgG4 associated cholangiopathy (IAC), autoimmune hepatitis (AIH), non-alcoholic fatty liver disease (NAFLD), hepatitis B and C, and drug-induced hepatotoxicity. The aim of this review is to examine our current knowledge of IBD - associated hepatobiliary EIMs and their treatment.
    DOI:  https://doi.org/10.26402/jpp.2021.5.01
  5. Hepatology. 2022 Feb 12.
    FGF4 protects the liver from non-alcoholic fatty liver disease by activating the AMPK-Caspase 6 signal axis.
    Lintao Song, Luyao Wang, Yushu Hou, Jie Zhou, Chuchu Chen, Xianxi Ye, Wenliya Dong, Huan Gao, Yi Liu, Guanting Qiao, Tongtong Pan, Qiong Chen, Yu Cao, Fengjiao Hu, Zhiheng Rao, Yajing Chen, Yu Han, Minghua Zheng, Yongde Luo, Xiaokun Li, Yongping Chen, Zhifeng Huang.
      Non-alcoholic fatty liver disease (NAFLD) represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidences suggest that several fibroblast growth factors (FGFs) play important roles in diverse aspects of liver pathophysiology. Here we report a previously unappreciated role of FGF4 in the liver. Expression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepatic Fgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high-fat diet (HFD). By contrast, pharmacological administration of recombinant FGF4 (rFGF4) mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGFR4, which activates a downstream Ca2+ -CaMKKβ-dependent AMPK-Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage. In conclusion, our study identifies FGF4 as a novel stress-responsive regulator of liver pathophysiology that acts through an FGFR4-AMPK-Caspase 6 signal pathway, shedding lights on novel strategies for treating NAFLD and associated liver pathologies.
    DOI:  https://doi.org/10.1002/hep.32404
  6. Sci Rep. 2022 Feb 16. 12(1): 2571
    A robust gene expression signature for NASH in liver expression data.
    Yehudit Hasin-Brumshtein, Suraj Sakaram, Purvesh Khatri, Yudong D He, Timothy E Sweeney.
      Non-Alcoholic Fatty Liver Disease (NAFLD) is a progressive liver disease that affects up to 30% of worldwide population, of which up to 25% progress to Non-Alcoholic SteatoHepatitis (NASH), a severe form of the disease that involves inflammation and predisposes the patient to liver cirrhosis. Despite its epidemic proportions, there is no reliable diagnostics that generalizes to global patient population for distinguishing NASH from NAFLD. We performed a comprehensive multicohort analysis of publicly available transcriptome data of liver biopsies from Healthy Controls (HC), NAFLD and NASH patients. Altogether we analyzed 812 samples from 12 different datasets across 7 countries, encompassing real world patient heterogeneity. We used 7 datasets for discovery and 5 datasets were held-out for independent validation. Altogether we identified 130 genes significantly differentially expressed in NASH versus a mixed group of NAFLD and HC. We show that our signature is not driven by one particular group (NAFLD or HC) and reflects true biological signal. Using a forward search we were able to downselect to a parsimonious set of 19 mRNA signature with mean AUROC of 0.98 in discovery and 0.79 in independent validation. Methods for consistent diagnosis of NASH relative to NAFLD are urgently needed. We showed that gene expression data combined with advanced statistical methodology holds the potential to serve basis for development of such diagnostic tests for the unmet clinical need.
    DOI:  https://doi.org/10.1038/s41598-022-06512-0
  7. Front Immunol. 2022 ;13 819224
    CCR6 and CXCR6 Identify the Th17 Cells With Cytotoxicity in Experimental Autoimmune Encephalomyelitis.
    Lifei Hou, Koichi Yuki.
      Due to the plasticity of IL-17-producing CD4 T cells (Th17 cells), a long-standing challenge in studying Th17-driven autoimmune is the lack of specific surface marker to identify the pathogenic Th17 cells in vivo. Recently, we discovered that pathogenic CD4 T cells were CXCR6 positive in experimental autoimmune encephalomyelitis (EAE), a commonly used Th17-driven autoimmune model. Herein, we further revealed that peripheral CXCR6+CD4 T cells contain a functionally distinct subpopulation, which is CCR6 positive and enriched for conventional Th17 molecules (IL-23R and RORγt) and cytotoxic signatures. Additionally, spinal cord-infiltrating CD4 T cells were highly cytotoxic by expressing Granzyme(s) along with IFNγ and GM-CSF. Collectively, this study suggested that peripheral CCR6+CXCR6+CD4 T cells were Th17 cells with cytotoxic property in EAE model, and highlighted the cytotoxic granzymes for EAE pathology.
    Keywords:  CCR6; CXCR6; EAE; Multiple Sclerosis; Th17; cytotoxicity
    DOI:  https://doi.org/10.3389/fimmu.2022.819224
  8. Front Genet. 2021 ;12 785290
    Analysis and Visualization of Spatial Transcriptomic Data.
    Boxiang Liu, Yanjun Li, Liang Zhang.
      Human and animal tissues consist of heterogeneous cell types that organize and interact in highly structured manners. Bulk and single-cell sequencing technologies remove cells from their original microenvironments, resulting in a loss of spatial information. Spatial transcriptomics is a recent technological innovation that measures transcriptomic information while preserving spatial information. Spatial transcriptomic data can be generated in several ways. RNA molecules are measured by in situ sequencing, in situ hybridization, or spatial barcoding to recover original spatial coordinates. The inclusion of spatial information expands the range of possibilities for analysis and visualization, and spurred the development of numerous novel methods. In this review, we summarize the core concepts of spatial genomics technology and provide a comprehensive review of current analysis and visualization methods for spatial transcriptomics.
    Keywords:  cell-type identification; clustering; dimensionality reduction; single-cell RNA-seq (scRNA-seq); spatial expression pattern; spatial interaction; spatial transcriptomics; visualization
    DOI:  https://doi.org/10.3389/fgene.2021.785290
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