Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH,Journal of Hepatology

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Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH
Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-06-21 , DOI: 10.1016/j.jhep.2022.06.004
Tim Hendrikx ₁ , Florentina Porsch ₂ , Máté G Kiss ₂ , Dragana Rajcic ₂ , Nikolina Papac-Miličević ₂ , Constanze Hoebinger ₂ , Laura Goederle ₂ , Anastasiya Hladik ₃ , Lisa E Shaw ₄ , Hauke Horstmann ₅ , Sylvia Knapp ₃ , Sophia Derdak ₆ , Martin Bilban ₇ , Lena Heintz ₈ , Marcin Krawczyk ₉ , Rafael Paternostro ₁₀ , Michael Trauner ₁₀ , Matthias Farlik ₄ , Dennis Wolf ₅ , Christoph J Binder ₂

Affiliation

Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria; Department of Molecular Genetics, NUTRIM, Maastricht University, Maastricht, the Netherlands.
Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria.
Department of Medicine I, Laboratory of Infection Biology, Medical University Vienna, Vienna, Austria.
Department of Dermatology, Medical University Vienna, Vienna, Austria.
Department of Cardiology and Angiology I, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Core Facilities, Medical University of Vienna, Medical University Vienna, Vienna, Austria.
Department of Laboratory Medicine, KILM, Medical University Vienna, Vienna, Austria; Core Facilities, Medical University of Vienna, Medical University Vienna, Vienna, Austria.
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Laboratory of Metabolic Liver Diseases, Medical University of Warsaw, Warsaw, Poland.
Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria.

Background & Aims

Previous single-cell RNA-sequencing analyses have shown that Trem2-expressing macrophages are present in the liver during obesity, non-alcoholic steatohepatitis (NASH) and cirrhosis. Herein, we aimed to functionally characterize the role of bone marrow-derived TREM2-expressing macrophage populations in NASH.

Methods

We used bulk RNA sequencing to assess the hepatic molecular response to lipid-dependent dietary intervention in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single-cell sequencing were applied to functionally characterize the role of TREM2⁺ macrophage populations in NASH.

Results

We found that the hepatic transcriptomic profile during steatohepatitis mirrors the dynamics of recruited bone marrow-derived monocytes that already acquire increased expression of Trem2 in the circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels were superior to traditionally used laboratory parameters for distinguishing between different fatty liver disease stages in two separate clinical cohorts. Spatial transcriptomics revealed that TREM2⁺ macrophages localize to sites of hepatocellular damage, inflammation and fibrosis in the steatotic liver. Finally, using multiple murine models and in vitro experiments, we demonstrate that hematopoietic Trem2 deficiency causes defective lipid handling and extracellular matrix remodeling, resulting in exacerbated steatohepatitis, cell death and fibrosis.

Conclusions

Our study highlights the functional properties of bone marrow-derived TREM2⁺ macrophages and implies the clinical relevance of systemic soluble TREM2 levels in the context of NASH.

Lay summary

Our study defines the origin and function of macrophages (a type of immune cell) that are present in the liver and express a specific protein called TREM2. We find that these cells have an important role in protecting against non-alcoholic steatohepatitis (a progressive form of fatty liver disease). We also show that the levels of soluble TREM2 in the blood could serve as a circulating marker of non-alcoholic fatty liver disease.

中文翻译：

可溶性 TREM2 水平反映 TREM2+ 巨噬细胞的募集和扩增，这些巨噬细胞定位于纤维化区域并限制 NASH

背景与目标

先前的单细胞 RNA 测序分析表明，在肥胖、非酒精性脂肪性肝炎 (NASH) 和肝硬化期间，肝脏中存在表达Trem2的巨噬细胞。在这里，我们旨在从功能上描述骨髓来源的 TREM2 表达巨噬细胞群在 NASH 中的作用。

方法

我们使用大量 RNA 测序来评估小鼠对脂质依赖性饮食干预的肝脏分子反应。空间映射、两种互补鼠模型中的骨髓移植和单细胞测序被用于从功能上表征 TREM2 ⁺巨噬细胞群在 NASH 中的作用。

结果

我们发现脂肪性肝炎期间的肝脏转录组谱反映了募集的骨髓来源的单核细胞的动态，这些单核细胞已经在循环中获得了增加的Trem2表达。Trem2表达增加反映在患有 NASH 的小鼠和人类中全身可溶性 TREM2 水平升高。此外，可溶性 TREM2 水平优于传统使用的实验室参数，用于区分两个独立临床队列中的不同脂肪肝疾病阶段。空间转录组学显示 TREM2 ⁺巨噬细胞定位于脂肪肝中的肝细胞损伤、炎症和纤维化部位。最后，使用多种小鼠模型和体外实验证明，造血Trem2缺乏会导致脂质处理缺陷和细胞外基质重塑，从而导致脂肪性肝炎加重、细胞死亡和纤维化。