bims-nastce 2022-02-06 papers

bims-nastce

Biomed News

on NASH and T cells

Issue of 2022–02–06
thirteen papers selected by
Petra Hirsova, Mayo Clinic College of Medicine

Identification of Liver Immune Microenvironment-Related Hub Genes in Liver of Biliary Atresia.
Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B.
Metabolic link between obesity and autoimmune diseases.
Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV.
TNF in the liver: targeting a central player in inflammation.
CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T-cells.
Lethal lipotoxicity for liver cancer therapy.
T Cell Responses to the Microbiota.
NASH: regulatory considerations for clinical drug development and U.S. FDA approval.
Peroxidasin deficiency re-programs macrophages toward pro-fibrolysis function and promotes collagen resolution in liver.
Immunopathology caused by impaired CD8+ T cell responses.
Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer.
IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation.

Front Pediatr. 2021 ;9 786422

Identification of Liver Immune Microenvironment-Related Hub Genes in Liver of Biliary Atresia.

Jiaxu Zhang, Yi Luo, Mingxuan Feng, Qiang Xia.

  Background: Biliary atresia (BA) is one of the most common and fatal abnormalities of newborns. Increasing evidences indicated that immunology was the critical part of the etiology. This research used a public gene expression database to explore the immune microenvironment of BA liver. Methods: The gene expression profiles GSE46960, GSE159720, and GSE15235, containing BA and normal liver gene expression data, were obtained from the Expression Omnibus Gene. We applied CIBERSORTx to quantify 22 subsets of immune cells in BA liver. The differentially expressed genes (DEGs) and immune cells were used to further explore their relationship with liver fibrosis and the inflammation status of BA. Results: The expression of immune-related genes CXCL6, CXCL8, CXCL10, CCL20, IL32, TGFB2, SPP1, and SLIT2 was significantly different between BA and normal liver, among which CXCL8 was the hub gene. Six of 22 immune cell proportions were significantly different between BA and normal liver. Specifically, M0 macrophages and resting memory CD4+ T cells were upregulated in BA liver compared with normal liver. Meanwhile, monocytes, resting natural killer (NK) cells, plasma cells, and regulatory T (Treg) cells were downregulated. A further correlation analysis revealed that SLIT2 and CXCL6 owned high positive correlation coefficients with fibrosis grade, while the proportion of resting NK cells was negatively correlated. Proportions of resting CD4+ memory T cells were strongly related to the inflammation grade of BA liver. Conclusion: Biliary atresia is a disease strongly correlated with immune response. Our results might provide a clue for further exploration of BA etiology, which may promote a potential prediction model based on immune infiltration features.

Keywords:  biliary atresia; gene expression profile; immune microenvironment; liver autoimmune disease; prognosis

DOI:  https://doi.org/10.3389/fped.2021.786422
Front Cardiovasc Med. 2021 ;8 812769

Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B.

Felix Sebastian Nettersheim, Simon Braumann, Kouji Kobiyama, Marco Orecchioni, Melanie Vassallo, Jacqueline Miller, Amal Ali, Payel Roy, Ryosuke Saigusa, Dennis Wolf, Klaus Ley, Holger Winkels.

  Atherosclerosis is a chronic, lipid-driven disease of medium sized arteries which causes myocardial infarction and stroke. Recently, an adaptive immune response against the plaque-associated autoantigen Apolipoprotein B100 (ApoB), the structural protein component of low-density lipoprotein, has been implicated in atherogenesis. In healthy individuals, CD4+ T cells responding to ApoB mainly comprised regulatory T cells, which confer immune tolerance and atheroprotection. Mice and patients with atherosclerosis harbor increased numbers of proatherogenic ApoB-reactive T-helper cell subsets. Given the lack of therapies targeting proatherogenic immunity, clarification of the underlying mechanisms is of high clinical relevance. T cells develop in the thymus, where strong autoreactive T cells are eliminated in the process of negative selection. Herein, we investigated whether the transcription factor autoimmune regulator (AIRE), which controls expression of numerous tissue-restricted self-antigens in the thymus, is involved in mediating tolerance to ApoB and whether Aire deficiency might contribute to atherogenesis. Mice deficient for Aire were crossbred to apolipoprotein E-deficient mice to obtain atherosclerosis-prone Aire -/- Apoe -/- mice, which were fed a regular chow diet (CD) or western-type diet (WD). CD4+ T cells responding to the ApoB peptide p6 were analyzed by flow cytometry. We demonstrate that Aire deficiency influences neither generation nor activation of ApoB-reactive T cells and has only minor and overall inconsistent impacts on their phenotype. Furthermore, we show that atherosclerotic plaque size is not affected in Aire -/- Apoe -/- compared to Aire +/+ Apoe -/-, irrespective of diet and gender. In conclusion, our data suggests that AIRE is not involved in regulating thymic expression of ApoB or atherosclerosis. Alternative mechanisms how ApoB-reactive CD4 T cells are selected in the thymus will have to be investigated.

Keywords:  T cells; adaptive immunity; antigen-specific; atherosclerosis; autoimmune regulator; dextramer; immune tolerance; thymic selection

DOI:  https://doi.org/10.3389/fcvm.2021.812769
Eur Cytokine Netw. 2021 Dec 01. 32(4): 64-72

Metabolic link between obesity and autoimmune diseases.

Jacek Karczewski, Aleksandra Zielińska, Rafał Staszewski, Piotr Eder, Agnieszka Dobrowolska.

  The abnormal accumulation of visceral adipose tissue in obesity is associated with metabolic changes that include altered glucose tolerance, insulin resistance, hyperlipidemia, and metabolic syndrome. Obesity also coincides with increased incidence of autoimmune diseases. Accumulating evidence suggest that prolonged metabolic overload related to overnutrition, influenced by genetic and epigenetic factors, might affect immunologic self-tolerance through changes in the energy metabolism of immune cells, particularly regulatory T (Treg) cells. A strong activation of nutrient-energy signaling pathways blocks the induction of the transcription factor forkhead P3 (FOXP3), a master regulator of Treg cells, consequently inhibiting their generation and proliferation, thereby promoting proinflammatory response. Expanding our knowledge on the topic, particularly on metabolic T cell flexibility in vivo will provide new insights that can be used to develop therapeutic strategies for various inflammatory diseases, including obesity and autoimmune diseases. Targeting specific metabolic pathways is emerging as an important approach to control immune response and maintain immunological homeostasis.

Keywords:  autoimmunity; cytokines; immunometabolism; lymphocyte metabolism; obesity

DOI:  https://doi.org/10.1684/ecn.2021.0474
Front Immunol. 2021 ;12 796898

Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV.

Hubaida Fuseini, Rita Smith, Cindy H Nochowicz, Joshua D Simmons, LaToya Hannah, Celestine N Wanjalla, Curtis L Gabriel, Mona Mashayekhi, Samuel S Bailin, Jessica L Castilho, Alyssa H Hasty, John R Koethe, Spyros A Kalams.

  While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4+ T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m2, is positively correlated with greater CD4+ T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4+ T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4+ T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4+ T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4+ T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4+ T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4+ T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4+ T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4+ T reconstitution in PLWH initiating ART.

Keywords:  CD4+ T cell; HIV; IL-17A; Ki67; body mass index; leptin; obesity

DOI:  https://doi.org/10.3389/fimmu.2021.796898
Semin Immunopathol. 2022 Feb 04.

TNF in the liver: targeting a central player in inflammation.

Gisa Tiegs, Andrea K Horst.

  Tumour necrosis factor-α (TNF) is a multifunctional cytokine. First recognized as an endogenous soluble factor that induces necrosis of solid tumours, TNF became increasingly important as pro-inflammatory cytokine being involved in the immunopathogenesis of several autoimmune diseases. In the liver, TNF induces numerous biological responses such as hepatocyte apoptosis and necroptosis, liver inflammation and regeneration, and autoimmunity, but also progression to hepatocellular carcinoma. Considering these multiple functions of TNF in the liver, we propose anti-TNF therapies that specifically target TNF signalling at the level of its specific receptors.

Keywords:  Apoptosis; Autoimmune hepatitis; Inflammation; Non-alcoholic fatty liver disease; Primary sclerosing cholangitis; TNF signalling; Viral hepatitis

DOI:  https://doi.org/10.1007/s00281-022-00910-2
Circulation. 2022 Feb 03.

CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T-cells.

Guoshuai Feng, Geetika Bajpai, Pan Ma, Andrew Koenig, Andrea Bredemeyer, Inessa Lokshina, Lulu Lai, Irmgard Förster, Florian Leuschner, Daniel Kreisel, Kory J Lavine.

Background: Recent studies have established that C-C chemokine receptor type 2 (CCR2) marks pro-inflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2+ monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation. Methods: We utilized mouse models of reperfused myocardial infarction (MI), angiotensin II and phenylephrine (AngII/PE) infusion, and diphtheria toxin (DT) cardiomyocyte ablation to investigate C-C chemokine ligand 17 (CCL17). We employed Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects. Results: We demonstrated that CCL17 is expressed in CCR2+ macrophages and cluster of differentiation (CD)11b+ conventional dendritic cells following MI, AngII/PE infusion and DT cardiomyocyte ablation. We elucidated the transcriptional signature of CCL17+ macrophages and dendritic cells and identified granulocyte macrophage-colony stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of signal transducer and activator of transcription 5 (STAT5) and canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Ccl17 deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function following MI and AngII/PE infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured Ccl17 knockout mice. Mechanistically, CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 activated both Gq and β-arrestin signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated β-arrestin signaling and Tregs migration. Finally, we provide evidence that Tregs mediated the protective effects of Ccl17 deletion on myocardial inflammation and adverse LV remodeling. Conclusions: Collectively, these findings identify CCL17 as a pro-inflammatory mediator of CCR2+ macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.055888
Nat Cancer. 2021 Feb;2(2): 138-140

Lethal lipotoxicity for liver cancer therapy.

Suchira Gallage, Jose Efren Barragan Avila, Mathias Heikenwalder.

DOI: https://doi.org/10.1038/s43018-021-00175-y
Annu Rev Immunol. 2022 Feb 03.

T Cell Responses to the Microbiota.

Ivaylo I Ivanov, Timur Tuganbaev, Ashwin N Skelly, Kenya Honda.

The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. We now appreciate that the coevolution of the immune system and the microbiota has led to development of a lush immunological decision tree downstream of microbial recognition, of which an inflammatory response is but one branch. In this review we discuss known T cell-microbe interactions in the gut and place them in the context of an algorithmic framework of recognition, context-dependent interpretation, and response circuits across multiple levels of microbial recognition resolution. The malleability of T cells in response to the microbiota presents an opportunity to edit immune response cellularity, identity, and functionality by utilizing microbiota-controlled pathways to promote human health. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-immunol-101320-011829
Acta Pharmacol Sin. 2022 Jan 21.

NASH: regulatory considerations for clinical drug development and U.S. FDA approval.

Brian E Harvey.

  Nonalcoholic fatty liver disease is a growing public health crisis, with phenotypes from nonalcoholic fatty liver to nonalcoholic steatohepatitis, currently known as NASH, which can progress to liver fibrosis and end stage cirrhosis. NASH is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus. There are still no U.S. FDA approved drugs or biological treatments for NASH or related liver diseases. Despite official agency guidance, the regulatory pathway to ultimate product approval is unclear, due to both the extra-hepatic factors that contribute to NASH, as well as the organizational structure of FDA, with its traditional separation of therapeutic indications within discrete review divisions. There is hope that continued evolution of the regulatory process will lead to the ability for clinical trial endpoints supporting NASH treatment approval to include both liver-based and traditional metabolic measures, independent of specific FDA division review.

Keywords:  FDA; NASH; U.S. Food & Drug Administration; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; patient focused drug development

DOI:  https://doi.org/10.1038/s41401-021-00832-z
Cell Mol Gastroenterol Hepatol. 2022 Jan 27. pii: S2352-345X(22)00015-7. [Epub ahead of print]

Peroxidasin deficiency re-programs macrophages toward pro-fibrolysis function and promotes collagen resolution in liver.

Mozhdeh Sojoodi, Derek J Erstad, Stephen C Barrett, Shadi Salloum, Shijia Zhu, Tongqi Qian, Selene Colon, Eric M Gale, Veronica Clavijo Jordan, Yongtao Wang, Shen Li, Bahar Ataeinia, Sasan Jalilifiroozinezhad, Michael Lanuti, Lawrence Zukerberg, Peter Caravan, Yujin Hoshida, Raymond T Chung, Gautam Bhave, Georg Lauer, Bryan C Fuchs, Kenneth K Tanabe.

   BACKGROUND & AIMS: During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix (ECM) proteins. ECM stabilization influences the speed of tissue recovery. Here, we studied the expression and function of Peroxidasin (PXDN), a peroxidase that uses H2O2 to cross-link collagen IV, during liver fibrosis progression and regression.
METHODS: Mouse models of liver fibrosis and cirrhosis patients were analyzed for the expression of PXDN in liver and serum. Pxdn-/- and Pxdn+/+ mice were either treated with CCl4 for 6 weeks to generate toxin-induced fibrosis or fed with a choline-deficient L-amino acid-defined high fat diet (CDAHFD) for 16 weeks to create nonalcoholic fatty liver disease (NAFLD) fibrosis. Liver histology, qPCR, collagen content, flowcytometry and immunostaining of immune cells, RNA-seq, and liver function tests were analyzed. In vivo imaging of liver ROS was performed using a redox-active iron complex, Fe-PyC3A.
RESULTS: In human and mouse cirrhotic tissue, PXDN is expressed by stellate cells and is secreted into fibrotic areas. In NAFLD patients, serum levels of PXDN increased significantly. In both mouse models of liver fibrosis, PXDN deficiency resulted in elevated monocyte and pro-fibrolysis macrophage recruitment into fibrotic bands and caused decreased accumulation of cross-linked collagens. In Pxdn-/- mice, collagen fibers were loosely organized, an atypical phenotype that is reversible upon macrophage depletion. Elevated ROS in Pxdn-/- livers was observed, which can result in activation of hypoxic signaling cascades and may affect signaling pathways involved in macrophage polarization such as TNF-α via NF-κB. Fibrosis resolution in Pxdn-/- mice was associated with significant decrease in collagen content and improved liver function.
CONCLUSION: PXDN deficiency is associated with increased ROS levels and a hypoxic liver microenvironment that can regulate recruitment and programming of pro-resolution macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest a novel pathway that is involved in the resolution of scar tissue.

Keywords:  Peroxidasin; fibrosis; liver; macrophages

DOI:  https://doi.org/10.1016/j.jcmgh.2022.01.015
Eur J Immunol. 2022 Jan 31.

Immunopathology caused by impaired CD8+ T cell responses.

Peter Aichele, Christoph Neumann-Haefelin, Stephan Ehl, Robert Thimme, Toni Cathomen, Melanie Boerries, Maike Hofmann.

  Recent findings indicate that many immunopathologies are at their roots a consequence of impaired immune responses ("too little" immunity) and not the result of primarily exaggerated immune responses ("too much" immunity). We have summarized this conceptional view as "IMPATH paradox". In this review, we will focus on impaired immune reactions in the context of CD8+ T cell-mediated immunopathologies. In particular, we will exemplify this concept in two disease models: Virus-triggered primary hemophagocytic lymphohistiocytosis, an inflammatory syndrome caused by genetically impaired cytolytic functions of T cells, and viral hepatitis, where T cell exhaustion is a major underlying mechanism for impaired effector functions. In both situations, T cells fail to eliminate the source of immune stimulation, which usually serves as an important negative feedback loop curtailing immune reactions. Persistent antigen presentation by antigen-presenting and/or infected cells results in continuous stimulation causing chronic inflammation and immunopathology mediated by residual T cell functions. Hence, immune stimulation or reconstitution rather than immune suppression may be strategies for therapeutic interventions. This article is protected by copyright. All rights reserved.

Keywords:  CD8+ T cells; T cell exhaustion; chronic viral hepatitis; immunopathology; primary hemophagocytic lymphohistiocytosis

DOI:  https://doi.org/10.1002/eji.202149528
Nat Cancer. 2020 Feb;1(2): 163-175

Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer.

CRUK IMAXT Grand Challenge Team

Genomic alterations shape cell phenotypes and the structure of tumor ecosystems in poorly defined ways. To investigate these relationships, we used imaging mass cytometry to quantify the expression of 37 proteins with subcellular spatial resolution in 483 tumors from the METABRIC cohort. Single-cell analysis revealed cell phenotypes spanning epithelial, stromal and immune types. Distinct combinations of cell phenotypes and cell-cell interactions were associated with genomic subtypes of breast cancer. Epithelial luminal cell phenotypes separated into those predominantly impacted by mutations and those affected by copy number aberrations. Several features of tumor ecosystems, including cellular neighborhoods, were linked to prognosis, illustrating their clinical relevance. In summary, systematic analysis of single-cell phenotypic and spatial correlates of genomic alterations in cancer revealed how genomes shape both the composition and architecture of breast tumor ecosystems and will enable greater understanding of the phenotypic impact of genomic alterations.

DOI: https://doi.org/10.1038/s43018-020-0026-6
Nat Immunol. 2022 Feb;23(2): 217-228

IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation.

Ana Amorim, Donatella De Feo, Ekaterina Friebel, Florian Ingelfinger, Cyrill Dimitri Anderfuhren, Sinduya Krishnarajah, Myrto Andreadou, Christina A Welsh, Zhaoyuan Liu, Florent Ginhoux, Melanie Greter, Burkhard Becher.

During inflammation, Ly6Chi monocytes are rapidly mobilized from the bone marrow (BM) and are recruited into inflamed tissues, where they undergo monocyte-to-phagocyte transition (MTPT). The in vivo developmental trajectories of the MTPT and the contribution of individual cytokines to this process remain unclear. Here, we used a murine model of neuroinflammation to investigate how granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFNγ), two type 1 cytokines, controlled MTPT. Using genetic fate mapping, gene targeting and high-dimensional single-cell multiomics analyses, we found that IFNγ was essential for the gradual acquisition of a mature inflammatory phagocyte phenotype in Ly6Chi monocytes, while GM-CSF was required to license interleukin-1β (IL-1β) production, phagocytosis and oxidative burst. These results suggest that the proinflammatory cytokine environment guided MTPT trajectories in the inflamed central nervous system (CNS) and indicated that GM-CSF was the most prominent target for the disarming of monocyte progenies during neuroinflammation.

DOI: https://doi.org/10.1038/s41590-021-01117-7