bims-nastce 2021-07-11 papers

Zhonghua Gan Zang Bing Za Zhi. 2021 Jun 20. 29(6): 595-599

[Mechanism of T lymphocyte subsets in the malignant transformation of non-alcoholic fatty liver disease].

W X Ye, Y Liu, X Y Wang, D F Yao, M Yao.

Nonalcoholic fatty liver disease is becoming the main cause of global liver disease-related morbidity and mortality. Notably, its pathological mechanism is complicated and not yet fully understood. Therefore, immune regulation is undoubtedly an important link in its pathogenesis, especially the change of T lymphocyte subsets. This article introduces the research progress of T lymphocytes involved in steatosis, inflammation, fibrosis, malignant transformation and immunotherapy.

Keywords: Chronic liver disease; Cluster of differentiation; Non-alcoholic fatty liver disease; T lymphocyte

DOI: https://doi.org/10.3760/cma.j.cn501113-20201029-00586

Zhonghua Gan Zang Bing Za Zhi. 2021 Jun 20. 29(6): 505-509

[Role of gut-liver-immune axis in the pathogenesis of nonalcoholic steatohepatitis].

L Shao, Y Song, J P Shi.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. Liver cirrhosis, liver cancer and a variety of extrahepatic chronic diseases are important risk factors for NAFLD. Currently, there is still a lack of effective therapeutic drugs. Liver inflammation is a key driving factor for the progression of NAFLD, so regulating liver inflammation may provide a potential means to delay and reverse the progression of nonalcoholic steatohepatitis (NASH). Studies have found that the gut-liver-immune axis plays an important role in the progression of NASH. Gut microbiota can use its metabolites to induce glycolipid toxicity, oxidative stress and intestinal barrier damage, while bacterial components such as lipopolysaccharides, peptidoglycans, bacterial DNA and extracellular vesicles can translocate into the liver through the damaged intestinal barrier, causing excessive activation of immune cells, thus aggravating liver inflammation and promoting the progress of NASH. This paper focuses on the gut-liver-immune axis to analyze the gut microbiota mediated liver immunity and its mechanism in the occurrence and development of NASH, so as to lay a theoretical foundation for the research and development of new therapeutic strategies for NASH.

Keywords: Fatty liver; Gut-liver axis; Gut-liver-immune axis; Inflammation

DOI: https://doi.org/10.3760/cma.j.cn501113-20210430-00215

Semin Immunopathol. 2021 Jul 07.

The role of natural killer cells in liver inflammation.

A J Highton, I S Schuster, M A Degli-Esposti, M Altfeld.

The liver is an important immunological site that can promote immune tolerance or activation. Natural killer (NK) cells are a major immune subset within the liver, and therefore understanding their role in liver homeostasis and inflammation is crucial. Due to their cytotoxic function, NK cells are important in the immune response against hepatotropic viral infections but are also involved in the inflammatory processes of autoimmune liver diseases and fatty liver disease. Whether NK cells primarily promote pro-inflammatory or tolerogenic responses is not known for many liver diseases. Understanding the involvement of NK cells in liver inflammation will be crucial in effective treatment and future immunotherapeutic targeting of NK cells in these disease settings. Here, we explore the role that NK cells play in inflammation of the liver in the context of viral infection, autoimmunity and fatty liver disease.

Keywords: Autoimmune liver disease; Fatty liver disease; Liver inflammation; NK cells; Viral hepatitis

DOI: https://doi.org/10.1007/s00281-021-00877-6

Cell Rep. 2021 Jul 06. pii: S2211-1247(21)00708-7. [Epub ahead of print]36(1): 109332

Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells.

Louise Dupraz, Aurélie Magniez, Nathalie Rolhion, Mathias L Richard, Grégory Da Costa, Sothea Touch, Camille Mayeur, Julien Planchais, Allison Agus, Camille Danne, Chloé Michaudel, Madeleine Spatz, François Trottein, Philippe Langella, Harry Sokol, Marie-Laure Michel.

Gut interleukin-17A (IL-17)-producing γδ T cells are tissue-resident cells that are involved in both host defense and regulation of intestinal inflammation. However, factors that regulate their functions are poorly understood. In this study, we find that the gut microbiota represses IL-17 production by cecal γδ T cells. Treatment with vancomycin, a Gram-positive bacterium-targeting antibiotic, leads to decreased production of short-chain fatty acids (SCFAs) by the gut microbiota. Our data reveal that these microbiota-derived metabolites, particularly propionate, reduce IL-17 and IL-22 production by intestinal γδ T cells. Propionate acts directly on γδ T cells to inhibit their production of IL-17 in a histone deacetylase-dependent manner. Moreover, the production of IL-17 by human IL-17-producing γδ T cells from patients with inflammatory bowel disease (IBD) is regulated by propionate. These data contribute to a better understanding of the mechanisms regulating gut γδ T cell functions and offer therapeutic perspectives of these cells.

Keywords: IL-17; SCFA; T cells; gut; propionate; γδ

DOI: https://doi.org/10.1016/j.celrep.2021.109332

Cell Metab. 2021 Jul 02. pii: S1550-4131(21)00275-8. [Epub ahead of print]

Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication.

Anne Loft, Ana Jimena Alfaro, Søren Fisker Schmidt, Felix Boel Pedersen, Mike Krogh Terkelsen, Michele Puglia, Kan Kau Chow, Annette Feuchtinger, Maria Troullinaki, Adriano Maida, Gretchen Wolff, Minako Sakurai, Riccardo Berutti, Bilgen Ekim Üstünel, Peter Nawroth, Kim Ravnskjaer, Mauricio Berriel Diaz, Blagoy Blagoev, Stephan Herzig.

Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy.

Keywords: Cell type-specific profiling; ELF3; GLIS2; genomic reprogramming; hepatocytes; liver fibrosis; metabolic-associated fatty liver disease; nonalcoholic steatohepatitis; transcription factor networks

DOI: https://doi.org/10.1016/j.cmet.2021.06.005

J Hepatol. 2021 Jun 30. pii: S0168-8278(21)01848-1. [Epub ahead of print]

Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

Lichun Ma, Limin Wang, Subreen A Khatib, Ching-Wen Chang, Sophia Heinrich, Dana A Dominguez, Marshonna Forgues, Julián Candia, Maria O Hernandez, Michael Kelly, Yongmei Zhao, Bao Tran, Jonathan M Hernandez, Jeremy L Davis, David E Kleiner, Bradford J Wood, Tim F Greten, Xin Wei Wang.

BACKGROUND & AIMS: Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Here, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis.
METHODS: We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled for interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA.
RESULTS: Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T-cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer.
CONCLUSIONS: Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy.
LAY SUMMARY: Intratumor molecular heterogeneity is a key feature of tumorigenesis, and is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.

Keywords: Functional clonality; Liver cancer; Osteopontin; Single cell; T cells; Tumor cell state; Tumor evolution; Tumor microenvironments; Tumor transcriptomic heterogeneity

DOI: https://doi.org/10.1016/j.jhep.2021.06.028

Semin Liver Dis. 2021 Jul 07.

Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity.

Marco Arrese, Juan P Arab, Francisco Barrera, Benedikt Kaufmann, Luca Valenti, Ariel E Feldstein.

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.

DOI: https://doi.org/10.1055/s-0041-1730927