Metabolic reprogramming in liver fibrosis

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(7), P. 1439 - 1455

Published: May 31, 2024

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident non-resident heterogeneous cell populations, ultimately leading to deposition extracellular matrix organ failure. Shifts phenotypes functions involve pronounced transcriptional protein synthesis changes that require adaptations cellular substrate metabolism, including glucose lipid resembling associated the Warburg effect cancer cells. Cell activation are regulated by stress responses, unfolded response, endoplasmic reticulum stress, autophagy, ferroptosis, nuclear receptor signaling. These crucial for inflammatory fibrogenic macrophages, lymphoid cells, hepatic stellate Modulation these pathways, therefore, offers opportunities novel therapeutic approaches halt even reverse fibrosis progression.

Language: Английский

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Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis

Trends in Immunology, Journal Year: 2023, Volume and Issue: 44(12), P. 986 - 998

Published: Nov. 6, 2023

Language: Английский

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Immunology of human fibrosis

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(9), P. 1423 - 1433

Published: July 20, 2023

Language: Английский

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Friend or foe? The elusive role of hepatic stellate cells in liver cancer

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(10), P. 647 - 661

Published: Aug. 7, 2023

Language: Английский

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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(716)

Published: Oct. 4, 2023

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses global health threat because its potential to progress advanced fibrosis, leading cirrhosis and cancer. Recent advances in single-cell methodologies, refined models, genetic epigenetic insights have provided nuanced understanding MASH fibrogenesis, with substantial cellular heterogeneity livers providing potentially targetable cell-cell interactions behavior. Unlike mechanisms underlying fibrosis regression are still inadequately understood, although antifibrotic targets been recently identified. A treatment framework could lead noninvasive assessment targeted therapies preserve hepatocellular function restore the liver’s architectural integrity.

Language: Английский

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Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(12), P. 2610 - 2631

Published: Sept. 27, 2023

Abstract Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. To better understand cellular and molecular events shaping niches, we used a spontaneous breast cancer lung metastasis model to create single-cell atlas spanning different stages regions. We found that premetastatic lungs are infiltrated by inflammatory neutrophils monocytes, followed accumulation of suppressive macrophages with emergence metastases. Spatial profiling revealed metastasis-associated immune cells were present in core, exception TREM2+ regulatory uniquely enriched at invasive margin, consistent across both murine models human patient samples. These (Mreg) contribute formation an immune-suppressive niche, cloaking tumor surveillance. Our study provides compendium cell dynamics informing development metastasis-targeting Significance: Temporal spatial analysis new players modulating surveillance suppression. highlights distinct populations TREM2 as modulators microenvironment metastasis, key determinant defining pointing myeloid checkpoints improve therapeutic strategies. This article is featured Selected Articles Issue, p. 2489

Language: Английский

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Evidence and therapeutic implications of biomechanically regulated immunosurveillance in cancer and other diseases

Nature Nanotechnology, Journal Year: 2024, Volume and Issue: 19(3), P. 281 - 297

Published: Jan. 29, 2024

Language: Английский

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The “Domino effect” in MASLD: The inflammatory cascade of steatohepatitis

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

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Hepatic danger signaling triggers TREM2 ⁺ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(738)

Published: March 13, 2024

Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms MASH center on hepatocyte injury and the ensuing immune response within microenvironment. Recent work has implicated TREM2 + macrophages in various disease conditions, substantial induction NASH-associated (NAMs) serves a hallmark Despite this, through which NAMs contribute to pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) NAM-specific factor that exacerbates progression mice. Hepatic MS4A7 expression was strongly induced mouse human associated with severity injury. Whole-body myeloid-specific ablation Ms4a7 alleviated diet-induced pathologies male We demonstrate exposure lipid droplets (LDs), released upon steatotic hepatocytes, triggered NAM exacerbated MASH-associated MS4A7-dependent manner. Mechanistically, drove NLRP3 inflammasome activation via direct physical interaction shaped disease-associated cell states This reveals LD-MS4A7-NLRP3 axis driver provides insights into role pathogenesis.

Language: Английский

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Lipid-associated macrophages’ promotion of fibrosis resolution during MASH regression requires TREM2

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(35)

Published: Aug. 22, 2024

While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages MASH regression is poorly understood. Comparing progression vs regression, we identified specific subpopulations that are critical for MASH/fibrosis resolution. We elucidated restorative pathways and gene signatures define regression-associated establish importance TREM2 + regression. Liver-resident Kupffer cells lost replaced by four distinct monocyte-derived subpopulations. Trem2 expressed in two subpopulations: i) occupying cell niche (MoKC) ii) lipid-associated (LAM). In livers, no new transcriptionally subpopulation emerged. However, relative composition changed compared to MASH. MoKC was major MASH, they decreased LAM dominant subtype maintained expression. Both were enriched disease-resolving pathways. Absence restricted emergence LAMs formation hepatic crown-like structures. functionally important not only restricting MASH-fibrosis but also effective inflammation fibrosis. superior collagen degraders. Lack prevented elimination steatosis inactivation HSC indicating their significance coordination with other types liver. imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, degradation.

Language: Английский

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