Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis
Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis
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DOI：
10.1136/gutjnl-2019-318382
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发表时间：
2020-03-01
期刊：
影响因子：
24.5
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
--
作者：
Krenkel, Oliver;Hundertmark, Jana;Tacke, Frank
目的在肥胖相关性非酒精性脂肪性肝病（NAFLD）向脂肪性肝炎（NASH）发展过程中，骨髓源性髓系细胞以单核细胞和巨噬细胞的形式在肝脏内聚集。骨髓细胞包括异质亚群，饮食营养过剩可能会影响肝脏和骨髓中的巨噬细胞。因此，我们的目的是在深入的功能适应的骨髓细胞在fatty liver.Design我们采用单细胞RNA测序，全面评估的异质性骨髓细胞在肝脏和骨髓在NAFLD，通过分析C57 BL/6小鼠喂食高脂肪，高糖，高胆固醇的“西方饮食”16周。我们还表征了NAFLD驱动的巨噬细胞在体外的功能适应和他们的功能相关性在体内脂肪性hepatitis invivo.Results单细胞RNA测序确定不同的骨髓细胞簇在肝脏和骨髓。在这两个隔室中，单核细胞来源的群体在NASH受影响的小鼠中大量扩增。重要的是，在NAFLD进展过程中，肝脏髓样区室适应了独特的炎性表型，其典型特征在于巨噬细胞和树突状细胞亚群中炎性钙卫蛋白（S100 A8/A9）下调。这种独特的基因特征也在他们的骨髓前体中发现。NASH髓样表型主要通过体外暴露于脂肪酸的骨髓源性巨噬细胞来重现，依赖于Toll样受体4信号传导，并定义了对脂多糖刺激的特征性反应模式。这种印迹和稳定的NASH髓系免疫表型功能决定急性肝损伤（醋氨酚中毒）后的炎症反应在vivo.Conclusion肝髓系白细胞和它们的骨髓前体适应一个共同的和功能相关的炎症信号在NAFLD的进展。
Objective Bone marrow-derived myeloid cells accumulate in the liver as monocytes and macrophages during the progression of obesity-related non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH). Myeloid cells comprise heterogeneous subsets, and dietary overnutrition may affect macrophages in the liver and bone marrow. We therefore aimed at characterising in depth the functional adaptations of myeloid cells in fatty liver.Design We employed single-cell RNA sequencing to comprehensively assess the heterogeneity of myeloid cells in the liver and bone marrow during NAFLD, by analysing C57BL/6 mice fed with a high-fat, high-sugar, high-cholesterol 'Western diet' for 16 weeks. We also characterised NAFLD-driven functional adaptations of macrophages in vitro and their functional relevance during steatohepatitis in vivo.Results Single-cell RNA sequencing identified distinct myeloid cell clusters in the liver and bone marrow. In both compartments, monocyte-derived populations were largely expanded in NASH-affected mice. Importantly, the liver myeloid compartment adapted a unique inflammatory phenotype during NAFLD progression, exemplarily characterised by downregulated inflammatory calprotectin (S100A8/A9) in macrophage and dendritic cell subsets. This distinctive gene signature was also found in their bone marrow precursors. The NASH myeloid phenotype was principally recapitulated by in vitro exposure of bone marrow-derived macrophages with fatty acids, depended on toll-like receptor 4 signalling and defined a characteristic response pattern to lipopolysaccharide stimulation. This imprinted and stable NASH myeloid immune phenotype functionally determined inflammatory responses following acute liver injury (acetaminophen poisoning) in vivo.Conclusion Liver myeloid leucocytes and their bone marrow precursors adapt a common and functionally relevant inflammatory signature during NAFLD progression.