JHEP reports : innovation in hepatology · 2025
From model to man: Understanding Tregs' dual role in MASLD.
СтатьяНазвание и аннотация: Перевод в очереди
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Dywicki Janine, Buitrago-Molina Laura Elisa, Baumann Anna K, Davalos-Misslitz Ana C, Hendriks Celina M, Hupa-Breier Katharina L, Lieber Maren, Schlue Jerome, Blüher Matthias, Bantel Heike, Falk Christine S, Koenecke Christian, Wellhöner Freya, Heidrich Benjamin, Manns Michael P, Noyan Fatih, Wedemeyer Heiner, Taubert Richard, Jaeckel Elmar, Hardtke-Wolenski Matthias
Аннотация
BACKGROUND & AIMS: Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) affects around 30% of the world's population and is often associated with metabolic conditions such as obesity, diabetes and hypertension. Approximately 10-20% of metabolic dysfunction-associated steatotic liver disease cases progress to metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the risk of liver cancer. While intrahepatic immune responses involving CD4+ and CD8+ T cells are potential therapeutic targets, their role in the pathogenesis of MASH is not fully understood. Regulatory T cells (Tregs), whose involvement has been controversial, require further investigation.
METHODS: In this study, we investigated the impact of adaptive immunity on MASH using a high-fat/high-carbohydrate diet (HF-HCD) model in wild-type and Rag2-deficient C57BL/6 mice, supplemented with human liver samples.
RESULTS: Our results showed that HF-HCD induced glucose intolerance and MASH, independent of adaptive immunity. Surprisingly, HF-HCD increased intrahepatic Treg numbers and the Treg/Teff ratio but did not alleviate the disease; instead, this increase correlated with greater disease severity. With progressing metabolic inflammation, an increased proportion of Tregs also expressed IL-17, which correlated with more severe liver pathology.
CONCLUSIONS: The observed expansion of Tregs and the resulting increase in the Treg/Teff ratio did not protect against MASH but correlated with more severe disease in both mice and humans, consistent with a pro-inflammatory shift towards IL-17-producing (TH17-skewed) cells. These findings highlight the complex role of adaptive immunity in MASH progression and provide potential targets for future immunomodulatory therapies.
IMPACT AND IMPLICATIONS: Diet-induced steatohepatitis can develop without adaptive immunity, yet IL-17A-expressing Foxp3+ T regulatory cells (Tregs) and CD8+ T cells markedly amplify hepatocellular injury and fibrosis. By separating initiating (macrophage-driven) from amplifying (adaptive) immune signals, our study refines current pathogenic models and provides hepatologists and immunologists with stage-specific therapeutic targets. For clinicians and trial designers, the data indicate that stabilizing Tregs or selectively dampening pro-inflammatory T-cell subsets could complement metabolic interventions in metabolic dysfunction-associated steatotic liver disease/steatohepatitis, whereas indiscriminate Treg expansion might be counter-productive. Because the conclusions are drawn from a murine model, translation to humans will require validation in patient-derived tissues and non-invasive immune biomarkers.
METHODS: In this study, we investigated the impact of adaptive immunity on MASH using a high-fat/high-carbohydrate diet (HF-HCD) model in wild-type and Rag2-deficient C57BL/6 mice, supplemented with human liver samples.
RESULTS: Our results showed that HF-HCD induced glucose intolerance and MASH, independent of adaptive immunity. Surprisingly, HF-HCD increased intrahepatic Treg numbers and the Treg/Teff ratio but did not alleviate the disease; instead, this increase correlated with greater disease severity. With progressing metabolic inflammation, an increased proportion of Tregs also expressed IL-17, which correlated with more severe liver pathology.
CONCLUSIONS: The observed expansion of Tregs and the resulting increase in the Treg/Teff ratio did not protect against MASH but correlated with more severe disease in both mice and humans, consistent with a pro-inflammatory shift towards IL-17-producing (TH17-skewed) cells. These findings highlight the complex role of adaptive immunity in MASH progression and provide potential targets for future immunomodulatory therapies.
IMPACT AND IMPLICATIONS: Diet-induced steatohepatitis can develop without adaptive immunity, yet IL-17A-expressing Foxp3+ T regulatory cells (Tregs) and CD8+ T cells markedly amplify hepatocellular injury and fibrosis. By separating initiating (macrophage-driven) from amplifying (adaptive) immune signals, our study refines current pathogenic models and provides hepatologists and immunologists with stage-specific therapeutic targets. For clinicians and trial designers, the data indicate that stabilizing Tregs or selectively dampening pro-inflammatory T-cell subsets could complement metabolic interventions in metabolic dysfunction-associated steatotic liver disease/steatohepatitis, whereas indiscriminate Treg expansion might be counter-productive. Because the conclusions are drawn from a murine model, translation to humans will require validation in patient-derived tissues and non-invasive immune biomarkers.