Metabolic reprogramming in liver fibrosis

Cell Metabolism, Год журнала: 2024, Номер 36(7), С. 1439 - 1455

Опубликована: Май 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.

Язык: Английский

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Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis

Trends in Immunology, Год журнала: 2023, Номер 44(12), С. 986 - 998

Опубликована: Ноя. 6, 2023

Язык: Английский

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Immunology of human fibrosis

Nature Immunology, Год журнала: 2023, Номер 24(9), С. 1423 - 1433

Опубликована: Июль 20, 2023

Язык: Английский

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

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2023, Номер 20(10), С. 647 - 661

Опубликована: Авг. 7, 2023

Язык: Английский

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

Science Translational Medicine, Год журнала: 2023, Номер 15(716)

Опубликована: Окт. 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.

Язык: 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, Год журнала: 2023, Номер 13(12), С. 2610 - 2631

Опубликована: Сен. 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

Язык: Английский

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

Nature Nanotechnology, Год журнала: 2024, Номер 19(3), С. 281 - 297

Опубликована: Янв. 29, 2024

Язык: Английский

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

Science Translational Medicine, Год журнала: 2024, Номер 16(738)

Опубликована: Март 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.

Язык: Английский

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

European Journal of Immunology, Год журнала: 2024, Номер 54(4)

Опубликована: Фев. 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

Язык: Английский

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Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair

Immunity, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Our understanding of the functional heterogeneity resident versus recruited macrophages in diseased liver is limited. A population lipid-associated (LAMs) has been reported to populate alongside Kupffer cells (KCs). However, precise roles these distinct macrophage subsets remain elusive. Here, using proteogenomics, we have identified LAMs multiple models injury. Moreover, found that this phenotype not specific macrophages, as a subset KCs can also adopt LAM-like mouse and human liver. By combining genetic targeting populations, determined both play crucial tissue repair. Specifically, triggering receptor expressed on myeloid 2 (TREM2) expression either or required for efficient clearance dying cells, enhancing repair preventing exacerbated fibrosis.

Язык: Английский

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