THBS1+ macrophages fuel pathogenic inflammation in alcohol-associated liver disease.

چکیده اصلی

BACKGROUND: Alcohol-associated liver disease (ALD) is one of the most common chronic liver diseases worldwide, with a pathological spectrum ranging from simple steatosis to steatohepatitis and, ultimately, cirrhosis. Severe alcohol-associated hepatitis (sAH) arises acutely within this continuum as a rapidly developing inflammatory condition associated with high mortality and poor prognosis. METHODS: To investigate important cellular subpopulations, we integrated single-cell RNA sequencing (scRNA-seq) data from the peripheral blood and liver tissues of healthy individuals and patients with ALD (including those with alcoholic cirrhosis and sAH). A murine metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease (MetALD)-like model was established by combining a metabolic dysfunction-associated steatohepatitis-inducing diet with controlled ethanol exposure. The model was used for histopathological analyses, and CD45+ cells from peripheral blood and liver tissues were isolated for scRNA-seq. Analyses included cell composition profiling, differential expression, pathway enrichment, pseudotime trajectory inference, transcriptional regulatory network reconstruction, and cell-cell communication analysis. In parallel, we generated THBS1‑KO and IL15‑KO immortalized bone marrow-derived macrophages cell lines in vitro and conducted functional assays to validate their roles. RESULTS: ScRNA-seq data revealed significant enrichment of IL15+ monocytes and THBS1+​​​​ monocyte-derived macrophages (moMFs) in patients with sAH, both exhibiting highly proinflammatory characteristics. Pseudotime analysis indicated that circulating IL15+ monocytes could dynamically differentiate into hepatic THBS1+ moMFs. Pathological staining and scRNA-seq data from the MetALD mouse model yielded similar results, further confirming the dynamic evolution of IL15+​​​​ monocytes into THBS1+​​​​ moMFs. In vitro cellular experiments also substantiated the proinflammatory roles of THBS1 and IL15. CONCLUSIONS: Our study reveals that circulating IL15+​​​​ monocytes dynamically differentiate into hepatic THBS1+​​​​ moMFs, and the combined proinflammatory action of these subsets accelerates the progression of ALD.

ترجمه فارسی چکیده

بیماری کبدی مرتبط با الکل (ALD) یکی از شایع‌ترین بیماری‌های مزمن کبد در جهان است که طیفی از بیماری‌های از جمله سفت شدن چربی تا کبد چرب التهابی و نهایتاً سیروز را در بر می‌گیرد. التهاب کبدی شدید الکلی (sAH) به عنوان یک وضعیت التهابی سریع‌الظهور با مرگ‌ومیر بالا و پیش‌آگهی ضعیف ظاهر می‌شود. این مطالعه با استفاده از توالی‌یابی رنا تک‌سلولی (scRNA-seq) از خون و بافت کبد افراد سالم و بیماران ALD، و همچنین مدل موش‌های MetALD، به بررسی زیرجمعیت‌های سلولی مهم پرداخت. نتایج نشان داد که ماکروفاژهای ماکروفاژ-مشتق از مونوسیت‌های THBS1+ و مونوسیت‌های IL15+ در بیماران sAH غنی شده‌اند و دارای ویژگی‌های التهابی شدید هستند. تحلیل‌ها نشان داد که مونوسیت‌های IL15+ در گردش به ماکروفاژهای THBS1+ کبدی تغییر می‌دهند و این فرآیند در مدل موش نیز تایید شد. آزمایش‌های در vitro نیز نقش التهابی این سلول‌ها را تأیید کرد.

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