Hepatic Stellate Cell-Immune Interactions in NASH DOI Creative Commons
James K. Carter, Scott L. Friedman

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: June 9, 2022

Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of worldwide. steatohepatitis (NASH), a more aggressive presentation NAFLD, characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation heightened immune cell activity have emerged as hallmark features NASH key drivers fibrosis through activation hepatic stellate cells (HSCs). Recent advances in our understanding molecular cellular pathways highlighted extensive crosstalk between HSCs populations that strongly influences activity. Here, we review these findings, emphasizing roles immunity cell-cell interactions, exciting areas for future investigation.

Language: Английский

CXCR2 inhibition enables NASH-HCC immunotherapy DOI Creative Commons
Jack Leslie, John B. G. Mackey, Thomas Jamieson

et al.

Gut, Journal Year: 2022, Volume and Issue: 71(10), P. 2093 - 2106

Published: April 27, 2022

Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor sensitise ICI therapy. Neutrophil infiltration was characterised in human and mouse models of HCC. Late-stage intervention anti-PD1 and/or performed murine NASH-HCC. The tumour microenvironment by imaging mass cytometry, RNA-seq flow cytometry. Neutrophils expressing CXCR2, receptor crucial neutrophil recruitment acute-injury, are highly represented In lacking response ICI, the combination antagonist suppressed burden extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation CD8+ T numbers which anti-tumoural immunity, this confirmed loss therapeutic effect on genetic impairment myeloid recruitment, neutralisation XCR1-ligand XCL1 or depletion cells. Therapeutic benefit accompanied an unexpected increase tumour-associated (TANs) switched from protumour anti-tumour progenitor-like phenotype. Reprogrammed TANs were found direct contact cells clusters enriched for cytotoxic protease granzyme B. reprogramming not observed circulation indicative selectively influencing TANs. CXCR2-inhibition induces promotes

Language: Английский

Citations

125
Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD DOI
Simon Wabitsch, Justin McCallen, Olena Kamenyeva

et al.

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 77(3), P. 748 - 760

Published: April 1, 2022

Language: Английский

Citations

102
The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease DOI
Luis Antonio Díaz, Juan Pablo Arab, Alexandre Louvet

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(12), P. 764 - 783

Published: Aug. 15, 2023

Language: Английский

Citations

97
Understanding the cellular interactome of non-alcoholic fatty liver disease DOI Creative Commons
Sebastian Wallace, Frank Tacke, Robert F. Schwabe

et al.

JHEP Reports, Journal Year: 2022, Volume and Issue: 4(8), P. 100524 - 100524

Published: June 15, 2022

Summary

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. steatohepatitis (NASH), which can lead to cirrhosis, has become leading indication for transplantation both Europe and USA. Liver fibrosis consequence sustained, iterative injury, main determinant outcomes NASH. The possesses remarkable inherent plasticity, regress when injurious agent removed, thus providing opportunities alter long-term through therapeutic interventions. Although hepatocyte injury key driver NASH, multiple other cell lineages within hepatic fibrotic niche play major roles perpetuation inflammation, mesenchymal activation, extracellular matrix accumulation as well resolution. constituents this cellular interactome, how various subpopulations interact drive fibrogenesis an area active research. Important components include endothelial cells, macrophages, passaging immune populations myofibroblasts. In review, we will describe rapidly evolving technologies such single-cell genomics, spatial transcriptomics ligand-receptor analyses are transforming our understanding interactome NAFLD/NASH, new, high-resolution information being leveraged develop rational new therapies patients

Language: Английский

Citations

83
Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation DOI Creative Commons
Neda Yahoo, Michael Dudek, Percy A. Knolle

et al.

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 538 - 551

Published: March 7, 2023

The liver is the central metabolic organ of body, regulating energy and lipid metabolism, while also having potent immunological functions. Overwhelming capacity via obesity a sedentary lifestyle leads to hepatic accumulation, chronic necro-inflammation, enhanced mitochondrial/endoplasmic reticulum stress development non-alcoholic fatty disease (NAFLD), its more severe form steatohepatitis (NASH). Based on an improved understanding pathophysiological mechanisms, specifically targeting pathways prevent or slow down progression NAFLD cancer will become possible. Genetic/environmental factors are known contribute NASH cancer. complex pathophysiology NAFLD-NASH reflected by environmental factors, particularly gut microbiome products. NAFLD-associated HCC most often occurs in context chronically inflamed cirrhotic liver. Recognition alarmins metabolites derived from microbiota metabolically injured create strong inflammatory milieu supported innate adaptive immunity. Several recent studies indicate that steatosis induces auto-aggressive CD8+CXCR6+PD1+ T cells eliminate parenchymal non-parenchymal antigen-independent manner. This promotes damage pro-tumorigenic environment. possess exhausted, hyperactivated, resident phenotype; they trigger transition might be responsible for weaker responses immune checkpoint inhibitors - particular atezolizumab/bevacizumab. Here, we provide overview NASH-related inflammation/pathogenesis, focusing new discoveries role cells. review discusses preventive measures halt therapeutic strategies manage patients with NASH-HCC.

Language: Английский

Citations

71
Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies DOI Creative Commons
Maurizio Parola, Massimo Pinzani

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 95, P. 101231 - 101231

Published: Dec. 5, 2023

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury well persistent activation inflammatory response and fibrogenesis. fibrosis is a major determinant for disease (CLD) progression in the last two decades our understanding on molecular cellular mechanisms underlying fibrogenic CLD has dramatically improved, boosting pre-clinical studies clinical trials designed to find novel therapeutic approaches. From these several critical concepts have emerged, starting reveal complexity pro-fibrotic microenvironment which involves very complex, dynamic interrelated interactions between different hepatic extrahepatic cell populations. This review will offer first recapitulation established pathophysiological basic principles by intentionally focus attention NAFLD/NASH, metabolic-related form with high impact general population emerging leading cause worldwide. NAFLD/NASH-related pro-inflammatory profibrogenic be analysed information cells, mediators signalling pathways taken advantage methodological approaches techniques (single genomics, imaging mass cytometry, vitro two- three-dimensional models, etc.). We next overview recent advancement diagnostic prognostic tools, including serum biomarkers polygenic scores, support analysis biopsies. Finally, this provide current therapies treatment NAFLD/NASH patients.

Language: Английский

Citations

70
Mechanisms of organ fibrosis: Emerging concepts and implications for novel treatment strategies DOI
Isabella Lurje, Nadine T. Gaisa, Ralf Weiskirchen

et al.

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 92, P. 101191 - 101191

Published: May 24, 2023

Language: Английский

Citations

69
METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation DOI Creative Commons

Meilin Xue,

Lei Dong, Honghai Zhang

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Feb. 1, 2024

Abstract Background While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying CSC self-renewal remains elusive. We aim to characterize of Methyltransferase 16 (METTL16), recently identified RNA N 6 -methyladenosine (m A) methyltransferase, HCC development/maintenance, stemness, as well normal hepatogenesis. Methods Liver-specific Mettl16 conditional KO (cKO) mice were generated assess its pathogenesis Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis xenograft models utilized determine METTL16 initiation progression. A limiting dilution assay was evaluate frequency. Functionally essential targets revealed via integrative analysis multi-omics data, including RNA-seq, immunoprecipitation (RIP)-seq, ribosome profiling. Results is highly expressed CSCs depletion dramatically decreased frequency vitro vivo. significantly attenuated yet only slightly influenced Mechanistic studies, high-throughput sequencing, unveiled key regulator ribosomal (rRNA) maturation mRNA translation eukaryotic factor 3 subunit ( eIF3a ) transcript bona-fide target HCC. In addition, functionally regions by CRISPR gene tiling scan, which will pave way for development potential inhibitor(s). Conclusions Our findings highlight oncogenic promoting enhancing through augmenting efficiency.

Language: Английский

Citations

23
The “Domino effect” in MASLD: The inflammatory cascade of steatohepatitis DOI Open Access
Karlo Mladenić, Maja Lenartić, Sonja Marinović

et al.

European Journal of Immunology, Journal Year: 2024, Volume and Issue: 54(4)

Published: Feb. 5, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter the global adult population. A key event in pathophysiology MASLD development metabolic-associated steatohepatitis (MASH), which greatly increases chances developing cirrhosis and hepatocellular carcinoma. The underlying cause MASH multifactorial, but accumulating evidence indicates that inflammatory process hepatic microenvironment typically follows pattern can be roughly divided into three stages: (1) Detection hepatocyte stress by tissue-resident immune cells including γδ T CD4

Language: Английский

Citations

19
Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease DOI
Naoto Fujiwara, Naoto Kubota,

Émilie Crouchet

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(650)

Published: June 22, 2022

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts 409 NAFLD from multiple global regions, we defined and validated hepatic transcriptome serum secretome signatures predictive long-term HCC NAFLD. A 133-gene signature, prognostic signature (PLS)–NAFLD, predicted incident over up to 15 years longitudinal observation. High-risk PLS-NAFLD was associated IDO1 + dendritic cells dysfunctional CD8 T fibrotic portal tracts along impaired metabolic regulators. independent who were naïve (HCC incidence rates at 22.7 0% high- low-risk patients, respectively) or experienced (de novo recurrence 5 71.8 42.9% respectively). bioinformatically translated into a four-protein PLSec-NAFLD, which cohort HCC-naïve cirrhosis 37.6 Combination PLSec-NAFLD our previously etiology-agnostic PLSec-AFP yielded improved stratification. modified by bariatric surgery, lipophilic statin, inhibitor, suggesting that the can be used for drug discovery as surrogate end point chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific prediction facilitate translation NAFLD-directed chemoprevention.

Language: Английский

Citations

70