bims-nastce 2022-03-13 papers

bims-nastce

Biomed News

on NASH and T cells

Issue of 2022–03–13
thirteen papers selected by
Petra Hirsova, Mayo Clinic College of Medicine

NAFLD and the Gut-Liver Axis: Exploring an Undernutrition Perspective.
Chemokine-Driven Migration of Pro-Inflammatory CD4+ T Cells in CNS Autoimmune Disease.
Interleukin-17 Weakens the NAFLD/NASH Process by Facilitating Intestinal Barrier Restoration Depending on the Gut Microbiota.
The critical and diverse roles of CD4-CD8- double negative T cells in nonalcoholic fatty liver disease.
MAdCAM-1 Costimulates T Cells through Integrin α4β7 to Cause Gene Expression Events Resembling Costimulation through CD28.
Transcriptional switch of hepatocytes initiates macrophage recruitment and T cell suppression in endotoxemia.
Single-cell immunology: Past, present, and future.
scGate: marker-based purification of cell types from heterogeneous single-cell RNA-seq datasets.
Regulation of liver subcellular architecture controls metabolic homeostasis.
TraSig: inferring cell-cell interactions from pseudotime ordering of scRNA-Seq data.
Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.
Meta-analysis: Prevalence of, and risk factors for, non-alcoholic fatty liver disease in patients with inflammatory bowel disease.
Challenges and directions in studying cell-cell communication by extracellular vesicles.

Gastroenterology. 2022 Mar 03. pii: S0016-5085(22)00203-7. [Epub ahead of print]

NAFLD and the Gut-Liver Axis: Exploring an Undernutrition Perspective.

Kylynda C Bauer, Paula T Littlejohn, Victoria Ayala, Anna Creus-Cuadros, B Brett Finlay.

  Non-alcoholic fatty liver disease (NAFLD) is a chronic condition affecting one quarter of the global population. Although primarily linked to obesity and metabolic syndrome, undernutrition and the altered (dysbiotic) gut microbiome influence NAFLD progression. Both undernutrition and NAFLD prevalence are predicted to considerably rise, but how the undernourished gut microbiome contributes to hepatic pathophysiology remains far less studied. Here, we present undernutrition conditions with fatty liver features, including kwashiorkor and micronutrient deficiency (MND). We then review the gut microbiota-liver axis, highlighting key pathways linked to NAFLD progression within both overnutrition and undernutrition. To conclude, we identify challenges and collaborative possibilities of emerging multiomic research addressing the pathology and treatment of undernourished NAFLD.

Keywords:  NAFLD; gut microbiome; gut-liver axis; malnutrition; undernutrition

DOI:  https://doi.org/10.1053/j.gastro.2022.01.058
Front Immunol. 2022 ;13 817473

Chemokine-Driven Migration of Pro-Inflammatory CD4+ T Cells in CNS Autoimmune Disease.

Aaron H S Heng, Caleb W Han, Caitlin Abbott, Shaun R McColl, Iain Comerford.

  Pro-inflammatory CD4+ T helper (Th) cells drive the pathogenesis of many autoimmune conditions. Recent advances have modified views of the phenotype of pro-inflammatory Th cells in autoimmunity, extending the breadth of known Th cell subsets that operate as drivers of these responses. Heterogeneity and plasticity within Th1 and Th17 cells, and the discovery of subsets of Th cells dedicated to production of other pro-inflammatory cytokines such as GM-CSF have led to these advances. Here, we review recent progress in this area and focus specifically upon evidence for chemokine receptors that drive recruitment of these various pro-inflammatory Th cell subsets to sites of autoimmune inflammation in the CNS. We discuss expression of specific chemokine receptors by subsets of pro-inflammatory Th cells and highlight which receptors may be tractable targets of therapeutic interventions to limit pathogenic Th cell recruitment in autoimmunity.

Keywords:  EAE (experimental autoimmune encephalomyelitis); Th subsets; chemokine; migration; multiple sclerosis

DOI:  https://doi.org/10.3389/fimmu.2022.817473
mBio. 2022 Mar 10. e0368821

Interleukin-17 Weakens the NAFLD/NASH Process by Facilitating Intestinal Barrier Restoration Depending on the Gut Microbiota.

Shuying He, Shudan Cui, Wen Song, Yonghong Jiang, Hongsheng Chen, Dongjiang Liao, Xinpeng Lu, Jun Li, Xueqing Chen, Liang Peng.

  Interleukin-17 (IL-17) is associated with nonalcoholic fatty liver disease (NAFLD) and gut microbiota, and how IL-17 mediates the NAFLD/nonalcoholic steatohepatitis (NASH) process depending on the gut microbiota is unclear. We found that T helper 17 (TH17) cells were decreased in the small intestine in a methionine choline-deficient (MCD) diet-induced NASH model. IL-17-deficient (Il17-/-) mice showed alterations in intestinal microbiota, including the inhibition of probiotic growth and the overgrowth of certain pathogenic bacteria, and were prone to higher endotoxemia levels and more severe gastrointestinal barrier defects than wild-type (WT) mice. Furthermore, TH17 cells were responsible for restoring the intestinal barrier after administration of recombinant IL-17 to Il17-/- mice or injection of CD4+ T cells into a Rag1-/- mouse model. Additionally, transplantation of the microbiota from WT mice to Il17-/- mice restored the intestinal barrier. Notably, microbiota-depleted Il17-/- mice were resistant to MCD diet-induced intestinal barrier impairment. Fecal microbiota transplantation from Il17-/- mice to microbiota-depleted mice aggravated intestinal barrier impairment and then promoted the development of NASH. Collectively, this study showed that host IL-17 could strengthen intestinal mucosal barrier integrity and reduce dysbiosis-induced intestinal injury and secondary extraintestinal organ injury induced by a special diet. IMPORTANCE The morbidity of NASH has increased, with limited effective treatment options. IL-17 plays a protective role in the gut mucosa in high-fat-diet (HFD)-related metabolic disorders, and HFD-related microbiota dysbiosis is responsible for a decreased number of T helper 17 (TH17) cells in the lamina propria. The mechanism by which IL-17 mediates the NAFLD/NASH process depending on the gut microbiota is unclear. In our study, IL-17 originating from TH17 cells maintained intestinal barrier integrity and determined the outcomes of diet-related disease, which may be a target strategy for NAFLD/NASH.

Keywords:  endotoxemia; interleukin-17; intestinal barrier; microbiota dysbiosis; nonalcoholic steatohepatitis

DOI:  https://doi.org/10.1128/mbio.03688-21
Cell Mol Gastroenterol Hepatol. 2022 Mar 02. pii: S2352-345X(22)00049-2. [Epub ahead of print]

The critical and diverse roles of CD4-CD8- double negative T cells in nonalcoholic fatty liver disease.

Changying Li, Xiaonan Du, Zongshan Shen, Yunxiong Wei, Yaning Wang, Xiaotong Han, Hua Jin, Chunpan Zhang, Mengyi Li, Zhongtao Zhang, Songlin Wang, Dong Zhang, Guangyong Sun.

   BACKGROUND & AIMS: Hepatic inflammation is a hallmark of nonalcoholic fatty liver disease (NAFLD). Double negative T (DNT) cells are a unique subset of T lymphocytes that do not express CD4, CD8 or natural killer cell markers, and studies have suggested that DNT cells play critical and diverse roles in the immune system. However, the role of intrahepatic DNT cells in NAFLD is largely unknown.
METHODS: The proportions and RNA transcription profiling of intrahepatic DNT cells were compared between C57BL/6 mice fed with control diet or methionine-choline deficient diet (MCD) for 5 weeks. The function of DNT cells were test in vitro and in vivo.
RESULTS: The proportion of intrahepatic DNT cells was significantly increased in mice with diet induced NAFLD. In NAFLD mice, the proportion of intrahepatic TCRγδ+ DNT cells was increased along with elevated interleukin (IL)-17A; in contrast, the percentage of TCRαβ+ DNT cells was decreased, accompanied by reduced granzyme B (GZMB). TCRγδ+ DNT cell depletion resulted in lowered liver IL-17A levels and significantly alleviated NAFLD. Adoptive transfer of intrahepatic TCRαβ+ DNT cells from control mice increased intrahepatic CD4 and CD8 T cells apoptosis and inhibited NAFLD progression. Furthermore, we revealed that adrenic acid and arachidonic acid, harmful fatty acids that were enriched in the liver of the mice with NAFLD, could induce apoptosis of TCRαβ+ DNT cells and inhibit their immunosuppressive function and NF-κB or AKT signaling pathway activity. However, arachidonic acid facilitated IL-17A secretion by TCRγδ+ DNT cells, and the NF-κB signaling pathway was involved. Finally, we also confirmed the variation of intrahepatic TCRαβ+ DNT cells and TCRγδ+ DNT cells in human.
CONCLUSIONS: During NAFLD progression, TCRγδ+ DNT enhance IL-17A secretion and aggravate liver inflammation, while TCRαβ+ DNT decrease GZMB production and lead to weakened immunoregulatory function. Shifting of balance from TCRγδ+ DNT response to one that favors TCRαβ+ DNT regulation would be beneficial for the prevention and treatment of NAFLD.

Keywords:  GZMB; IL-17A; NAFLD; TCRαβ(+) DNT cells; TCRγδ(+) DNT cells

DOI:  https://doi.org/10.1016/j.jcmgh.2022.02.019
Immunohorizons. 2022 Mar 10. 6(3): 211-223

MAdCAM-1 Costimulates T Cells through Integrin α4β7 to Cause Gene Expression Events Resembling Costimulation through CD28.

Hannah A DeBerg, Andrew J Konecny, Donna M Shows, James D Lord.

Successful treatment of inflammatory bowel disease (IBD) with the anti-integrin α4β7 mAb vedolizumab suggests that interaction of this integrin with addressin mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is central to IBD pathogenesis. Although this was presumed to be due to an inhibition of lymphocyte trafficking to the gut, as has been observed in animal models, we report no depletion of CD4 T cells from the colonic mucosa as a consequence of vedolizumab treatment in humans, regardless of efficacy. Likewise, no upregulation of alternative trafficking mechanisms was observed as a consequence of therapy to suggest that this homeostasis is maintained in patients by a mechanistic escape from inhibition. Instead, we explore a role for MAdCAM-integrin interaction as a gut-specific costimulatory signal, demonstrating that it can replace CD28 ligation to activate human T cells in vitro. This activation through integrin α4β7 is mediated through the gut-restricted molecule MAdCAM-1, and it cannot be replicated by matrix molecules or proteins that bind other integrins. A detailed analysis of mRNA expression by human T cell subsets following suboptimal TCR stimulation in the presence or absence of CD28 versus MAdCAM-1 costimulation reveals marked similarity in the effect that these two signals have upon T cells, with temporal or quantitative differences detected in the expression of cytokines associated with Th17 cells or pyogenic inflammation. Thus, we describe an alternative costimulatory pathway for T cells in the intestine, through ligation of integrin α4β7 by MAdCAM-1, which may explain the therapeutic efficacy of vedolizumab and have implications concerning the treatment of IBD.

DOI: https://doi.org/10.4049/immunohorizons.2200009
J Hepatol. 2022 Mar 08. pii: S0168-8278(22)00136-2. [Epub ahead of print]

Transcriptional switch of hepatocytes initiates macrophage recruitment and T cell suppression in endotoxemia.

Xuejing Sun, Junru Wu, Lun Liu, Yuanyuan Chen, Yan Tang, Suzhen Liu, Hang Chen, Youxiang Jiang, Yuanyuan Liu, Hong Yuan, Yao Lu, Zhaoyang Chen, Jingjing Cai.

   BACKGROUND & AIMS: The liver plays crucial roles in the regulation of immune defense during acute systemic infections. However, the roles of liver cellular clusters and intercellular communication in the progression of endotoxemia have not been well-characterized.
METHODS: Single-cell RNA sequencing analysis was performed, and the transcriptomes of 19,795 single liver cells from healthy and endotoxic mice were profiled. The spatial and temporal changes in hepatocytes and nonparenchymal cell types were validated by multiplex immunofluorescence staining, bulk transcriptomic sequencing, or flow cytometry. Furthermore, we used an adeno-associated virus delivery system to confirm the major mechanisms mediating myeloid cell infiltration and T cell suppression in septic murine liver.
RESULTS: We identified a proinflammatory hepatocyte (PIH) subpopulation that developed primarily from periportal hepatocytes and to a lesser extent from pericentral hepatocytes and played key immunoregulatory roles in endotoxemia. Multicellular cluster modeling of ligand-receptor interactions revealed that PIHs play a crucial role in the recruitment of macrophages via the CCL2-CCR2 interaction. Recruited macrophages (RMs) released cytokines (e.g., IL6, TNFα, and IL17) to induce the expression of inhibitory ligands, such as PD-L1, on hepatocytes. Subsequently, RM-stimulated hepatocytes led to the suppression of CD4+ and memory T cell subsets partly via the PD-1/PD-L1 interaction in endotoxemia. Furthermore, sinusoidal endothelial cells expressed the highest levels of proapoptotic and inflammatory genes around the periportal zone. This pattern of gene expression facilitated increases in the number of fenestrations and infiltration of immune cells in the periportal zone.
CONCLUSIONS: Our study elucidates unanticipated aspects of the cellular and molecular effects on liver cells in endotoxemia at the single-cell level and provides a conceptual framework for the development of novel therapeutic approaches for acute infection.
LAY SUMMARY: The liver plays a crucial role in the regulation of immune defense during acute systemic infections. We identified a proinflammatory hepatocyte subpopulation, and the interactions of this subpopulation with RMs via CCL2-CCR2 signaling and CD4+ T cells via the PD1-PD-L1 pathway have pivotal roles in the immune response during endotoxemia. These novel findings provide a conceptual framework for the discovery of rational therapeutic targets in acute infection.

Keywords:  Endotoxemia; Hepatocytes; Liver; Macrophage recruitment; Monocyte Chemotactic Protein-1 (MCP-1); Programmed Death-Ligand 1 (PD-L1); Single-cell RNA sequencing; T cell suppression

DOI:  https://doi.org/10.1016/j.jhep.2022.02.028
Immunity. 2022 Mar 08. pii: S1074-7613(22)00086-3. [Epub ahead of print]55(3): 393-404

Single-cell immunology: Past, present, and future.

Florent Ginhoux, Adam Yalin, Charles Antoine Dutertre, Ido Amit.

The immune system is a complex, dynamic, and plastic ecosystem composed of multiple cell types that constantly sense and interact with their local microenvironment to protect from infection and maintain homeostasis. For over a century, great efforts and ingenuity have been applied to the characterization of immune cells and their microenvironments, but traditional marker-based and bulk technologies left key questions unanswered. In the past decade, the advent of single-cell genomic approaches has revolutionized our knowledge of the cellular and molecular makeup of the immune system. In this perspective, we outline the past, present, and future applications of single-cell genomics in immunology and discuss how the integration of multiomics at the single-cell level will pave the way for future advances in immunology research and clinical translation.

DOI: https://doi.org/10.1016/j.immuni.2022.02.006
Bioinformatics. 2022 Mar 08. pii: btac141. [Epub ahead of print]

scGate: marker-based purification of cell types from heterogeneous single-cell RNA-seq datasets.

Massimo Andreatta, Ariel J Berenstein, Santiago J Carmona.

: A common bioinformatics task in single-cell data analysis is to purify a cell type or cell population of interest from heterogeneous datasets. Here we present scGate, an algorithm that automatizes marker-based purification of specific cell populations, without requiring training data or reference gene expression profiles. scGate purifies a cell population of interest using a set of markers organized in a hierarchical structure, akin to gating strategies employed in flow cytometry. scGate outperforms state-of-the-art single-cell classifiers and it can be applied to multiple modalities of single-cell data (e.g. RNA-seq, ATAC-seq, CITE-seq). scGate is implemented as an R package and integrated with the Seurat framework, providing an intuitive tool to isolate cell populations of interest from heterogeneous single-cell datasets.
AVAILABILITY: R package source code and reproducible tutorials are available at https://github.com/carmonalab/scGate.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btac141
Nature. 2022 Mar 09.

Regulation of liver subcellular architecture controls metabolic homeostasis.

Güneş Parlakgül, Ana Paula Arruda, Song Pang, Erika Cagampan, Nina Min, Ekin Güney, Grace Yankun Lee, Karen Inouye, Harald F Hess, C Shan Xu, Gökhan S Hotamışlıgil.

Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 105 µm3) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy1,2 imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets3 and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.

DOI: https://doi.org/10.1038/s41586-022-04488-5
Genome Biol. 2022 Mar 07. 23(1): 73

TraSig: inferring cell-cell interactions from pseudotime ordering of scRNA-Seq data.

Dongshunyi Li, Jeremy J Velazquez, Jun Ding, Joshua Hislop, Mo R Ebrahimkhani, Ziv Bar-Joseph.

  A major advantage of single cell RNA-sequencing (scRNA-Seq) data is the ability to reconstruct continuous ordering and trajectories for cells. Here we present TraSig, a computational method for improving the inference of cell-cell interactions in scRNA-Seq studies that utilizes the dynamic information to identify significant ligand-receptor pairs with similar trajectories, which in turn are used to score interacting cell clusters. We applied TraSig to several scRNA-Seq datasets and obtained unique predictions that improve upon those identified by prior methods. Functional experiments validate the ability of TraSig to identify novel signaling interactions that impact vascular development in liver organoids.Software https://github.com/doraadong/TraSig .

Keywords:  Cell-cell interactions; Development; Gene expression

DOI:  https://doi.org/10.1186/s13059-022-02629-7
Sci Transl Med. 2022 Mar 09. 14(635): eabj6879

Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.

Christian Schwartz, Viviane Schmidt, Andrea Deinzer, Heike C Hawerkamp, Emily Hams, Jasmin Bayerlein, Ole Röger, Moritz Bailer, Christian Krautz, Amr El Gendy, Moustafa Elshafei, Helen M Heneghan, Andrew E Hogan, Donal O'Shea, Padraic G Fallon.

Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.

DOI: https://doi.org/10.1126/scitranslmed.abj6879
Aliment Pharmacol Ther. 2022 Mar 11.

Meta-analysis: Prevalence of, and risk factors for, non-alcoholic fatty liver disease in patients with inflammatory bowel disease.

Mohammad Zamani, Shaghayegh Alizadeh-Tabari, Siddharth Singh, Rohit Loomba.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is found in inflammatory bowel disease (IBD). However, uncertainties remain on the magnitude of the association.
AIMS: To explore systematically the prevalence of, and risk factors for, NAFLD in IBD patients.
METHODS: We searched medical literature using Embase, PubMed, Web of Science, Scopus and ProQuest, from inception to September 30, 2021. We included observational studies reporting the prevalence of NAFLD in ≥50 adult patients with IBD. Diagnosis of NAFLD could be based on imaging, histopathology, and/or hepatic steatosis index. Sex, age, body mass index (BMI), diabetes, hypertension, dyslipidemia, prior surgery (bowel resection), corticosteroids, biologics and immunomodulators were assessed as potential risk factors for NAFLD.
RESULTS: Of 1893 citations, 44 eligible studies were finally included, comprising 14 947 subjects from 18 different countries. Pooled prevalence of NAFLD was 30.7% (95% confidence interval [CI] 26.5-34.9) in patients with IBD worldwide, which varied regionally. No significant difference was observed in the odds ratio (OR) of NAFLD among Crohn's disease (CD) patients compared with ulcerative colitis (UC) patients (1.16, 95% CI 0.93-1.44). Risk of NAFLD was almost twice as high in patients with IBD as in healthy subjects (OR 1.96, 95% CI 1.13-3.41). Age (adjusted OR 1.03, 95% CI 1.01-1.05) and BMI (adjusted OR 1.27, 95% CI 1.22-1.32) were statistically significantly associated with increased risk of NAFLD. The pooled prevalence of advanced liver fibrosis in IBD patients with NAFLD was 13.6% (95% CI 7.6-19.7) based on six studies.
CONCLUSION: Up to one-third of patients with IBD experienced NAFLD worldwide. The risk of NAFLD was two times higher in IBD patients versus healthy subjects.

DOI: https://doi.org/10.1111/apt.16879
Nat Rev Mol Cell Biol. 2022 Mar 08.

Challenges and directions in studying cell-cell communication by extracellular vesicles.

Guillaume van Niel, David R F Carter, Aled Clayton, Daniel W Lambert, Graça Raposo, Pieter Vader.

Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these.

DOI: https://doi.org/10.1038/s41580-022-00460-3