bims-nastce 2022-01-16 papers

Issue of 2022‒01‒16
seven papers selected by
Petra Hirsova
Mayo Clinic College of Medicine

Hepatology. 2022 Jan 12.

T Cells: Friends and Foes in NASH Pathogenesis and Hepatocarcinogenesis.

Pierluigi Ramadori, Shing Kam, Mathias Heikenwalder.

In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multi-factorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to single-cell level. However, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune check-point inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of the innate immune response in the hepatic NAFLD microenvironment, only in the last decade novel critical roles were unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune-microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for the resistance to anti-cancer therapy. In this article, we will review the specific functions of several T-cell populations involved in NAFLD and NAFLD-driven HCC. We will illustrate the cellular cross talk with other immune cells, the regulatory networks or stimulatory effects of these interactions and the role of the metabolic microenvironment in influencing immune-cell functionality. Finally, we will present the pros and cons of the current therapeutic strategies against NAFLD-related HCC and delineate possible novel approaches for the future.

DOI: https://doi.org/10.1002/hep.32336

Cell Mol Gastroenterol Hepatol. 2022 Jan 11. pii: S2352-345X(22)00007-8. [Epub ahead of print]

Liver steatosis is a driving factor of inflammation.

Raja Gopal Reddy Mooli, Sadeesh K Ramakrishnan.

Keywords: NAFLD; NASH; Steatosis; inflammation; lipotoxicity; macrophages

DOI: https://doi.org/10.1016/j.jcmgh.2022.01.007

Commun Biol. 2022 01 11. 5(1): 21

InterCellar enables interactive analysis and exploration of cell-cell communication in single-cell transcriptomic data.

Marta Interlandi, Kornelius Kerl, Martin Dugas.

Deciphering cell-cell communication is a key step in understanding the physiology and pathology of multicellular systems. Recent advances in single-cell transcriptomics have contributed to unraveling the cellular composition of tissues and enabled the development of computational algorithms to predict cellular communication mediated by ligand-receptor interactions. Despite the existence of various tools capable of inferring cell-cell interactions from single-cell RNA sequencing data, the analysis and interpretation of the biological signals often require deep computational expertize. Here we present InterCellar, an interactive platform empowering lab-scientists to analyze and explore predicted cell-cell communication without requiring programming skills. InterCellar guides the biological interpretation through customized analysis steps, multiple visualization options, and the possibility to link biological pathways to ligand-receptor interactions. Alongside convenient data exploration features, InterCellar implements data-driven analyses including the possibility to compare cell-cell communication from multiple conditions. By analyzing COVID-19 and melanoma cell-cell interactions, we show that InterCellar resolves data-driven patterns of communication and highlights molecular signals through the integration of biological functions and pathways. We believe our user-friendly, interactive platform will help streamline the analysis of cell-cell communication and facilitate hypothesis generation in diverse biological systems.

DOI: https://doi.org/10.1038/s42003-021-02986-2

Cell Mol Gastroenterol Hepatol. 2022 Jan 11. pii: S2352-345X(22)00006-6. [Epub ahead of print]

Inflammation: the straw that broke the NAFLD liver!

Reben Raeman.

Keywords: NAFLD; NASH; gut permeability; inflammation; microbiome; steatosis

DOI: https://doi.org/10.1016/j.jcmgh.2022.01.006

Blood Adv. 2022 Jan 11. pii: bloodadvances.2021006084. [Epub ahead of print]

Single cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ T cell lineage that induces GI tract GVHD.

Clint Piper, Emma Hainstock, Cheng Yin-Yuan, Yao Chen, Achia Khatun, Moujtaba Kasmani, John Evans, James A Miller, Jack Gorski, Weiguo Cui, William R Drobyski.

Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft versus host disease (GVHD). CD4+ T cells that produce GM-CSF have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if there exists a unique CD4+ GM-CSF+ subset that differs from other defined T helper (TH) subtypes. Using single cell RNA sequencing analysis, we identified two CD4+ GM-CSF+ T cell populations that arose during GVHD and were distinguishable by the presence or absence of IFN-γ co-expression. CD4+ GM-CSF+ IFN-γ- T cells which emerged preferentially in the colon had a distinct transcriptional profile, employed unique gene regulatory networks, and possessed a non-overlapping TCR repertoire when compared to CD4+ GM-CSF+ IFN-γ+ T cells as well as all other transcriptionally defined CD4+ T cell populations in the colon. Functionally, this CD4+ GM-CSF+ T cell population contributed to pathological damage in the GI tract which was critically dependent upon signaling through the IL-7 receptor but was independent of type 1 interferon signaling. Thus, these studies help to unravel heterogeneity within CD4+ GM-CSF+ T cells that arise during GVHD and define a developmentally distinct colitogenic TH GM-CSF+ subset that mediates immunopathology.

DOI: https://doi.org/10.1182/bloodadvances.2021006084

Cell. 2022 Jan 05. pii: S0092-8674(21)01481-1. [Epub ahead of print]

Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches.

The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.

Keywords: CITE-seq; Kupffer cell; NAFLD; across species; atlas; lipid-associated macrophage; liver; multi-omic; proteogenomic; spatial transcriptomics

DOI: https://doi.org/10.1016/j.cell.2021.12.018

Front Immunol. 2021 ;12 742584

Glucose but Not Fructose Alters the Intestinal Paracellular Permeability in Association With Gut Inflammation and Dysbiosis in Mice.

Xufei Zhang, Magali Monnoye, Mahendra Mariadassou, Fabienne Beguet-Crespel, Nicolas Lapaque, Christine Heberden, Veronique Douard.

A causal correlation between the metabolic disorders associated with sugar intake and disruption of the gastrointestinal (GI) homeostasis has been suggested, but the underlying mechanisms remain unclear. To unravel these mechanisms, we investigated the effect of physiological amounts of fructose and glucose on barrier functions and inflammatory status in various regions of the GI tract and on the cecal microbiota composition. C57BL/6 mice were fed chow diet and given 15% glucose or 15% fructose in drinking water for 9 weeks. We monitored caloric intake, body weight, glucose intolerance, and adiposity. The intestinal paracellular permeability, cytokine, and tight junction protein expression were assessed in the jejunum, cecum, and colon. In the cecum, the microbiota composition was determined. Glucose-fed mice developed a marked increase in total adiposity, glucose intolerance, and paracellular permeability in the jejunum and cecum while fructose absorption did not affect any of these parameters. Fructose-fed mice displayed increased circulation levels of IL6. In the cecum, both glucose and fructose intake were associated with an increase in Il13, Ifnγ, and Tnfα mRNA and MLCK protein levels. To clarify the relationships between monosaccharides and barrier function, we measured the permeability of Caco-2 cell monolayers in response to IFNγ+TNFα in the presence of glucose or fructose. In vitro, IFNγ+TNFα-induced intestinal permeability increase was less pronounced in response to fructose than glucose. Mice treated with glucose showed an enrichment of Lachnospiracae and Desulfovibrionaceae while the fructose increased relative abundance of Lactobacillaceae. Correlations between pro-inflammatory cytokine gene expression and bacterial abundance highlighted the potential role of members of Desulfovibrio and Lachnospiraceae NK4A136 group genera in the inflammation observed in response to glucose intake. The increase in intestinal inflammation and circulating levels of IL6 in response to fructose was observed in the absence of intestinal permeability modification, suggesting that the intestinal permeability alteration does not precede the onset of metabolic outcome (low-grade inflammation, hyperglycemia) associated with chronic fructose consumption. The data also highlight the deleterious effects of glucose on gut barrier function along the GI tract and suggest that Desulfovibrionaceae and Lachnospiraceae play a key role in the onset of GI inflammation in response to glucose.

Keywords: Caco-2; Desulfovibrio; fructose; glucose; paracellular permeability; pro-inflammatory cytokines

DOI: https://doi.org/10.3389/fimmu.2021.742584