Macrophage autophagy protects against liver fibrosis in mice
Macrophage autophagy protects against liver fibrosis in mice
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DOI：
10.1080/15548627.2015.1058473
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发表时间：
2015-08-01
期刊：
影响因子：
13.3
通讯作者：
Teixeira-Clerc, Fatima
中科院分区：
文献类型：
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作者：
Lodder, Jasper;Denaes, Timothe;Teixeira-Clerc, Fatima
自噬是细胞组分的溶酶体降解途径，在巨噬细胞中显示出吞噬特性。巨噬细胞通过释放促进肝细胞凋亡的介质，促进炎性细胞募集和肝纤维化细胞的活化，在慢性肝损伤中起关键作用。在这里，我们研究了巨噬细胞自噬是否可以防止慢性肝损伤。在骨髓谱系中具有自噬基因Atg 5突变的小鼠（Atg 5（fl/fl）LysM-Cre小鼠，称为atg 5（-/-））及其野生型（Atg 5（fl/fl），称为WT）同窝出生的小鼠中进行实验。腹腔注射四氯化碳诱导肝纤维化。在腹膜巨噬细胞与肝肌成纤维细胞的培养物或共培养物中进行体外研究。与WT同窝出生小鼠相比，暴露于四氯化碳长期给药的atg 5（-/-）小鼠显示出更高的肝脏IL 1A和IL 1B水平以及与肝损伤加重相关的炎性细胞募集增强。此外，atg 5（-/-）小鼠更容易发生肝纤维化，如增强的基质和纤维化细胞积聚所示。来自atg 5（-/-）小鼠的巨噬细胞分泌更高水平的活性氧（ROS）诱导的IL 1A和IL 1B。此外，暴露于atg 5（-/-）小鼠巨噬细胞条件培养基的肝肌成纤维细胞显示促纤维化基因表达增加;当中和atg 5（-/-）巨噬细胞条件培养基中的IL 1A和IL 1B时，这种作用减弱。最后，给四氯化碳暴露的atg 5（-/-）小鼠施用重组IL 1 RN（白细胞介素1受体拮抗剂）减弱了肝损伤和纤维化，确定IL 1A/B是巨噬细胞自噬失效的有害作用的中心介质。这些结果揭示了巨噬细胞自噬作为一种新的调节肝纤维化的信号通路。
Autophagy is a lysosomal degradation pathway of cellular components that displays antiinflammatory properties in macrophages. Macrophages are critically involved in chronic liver injury by releasing mediators that promote hepatocyte apoptosis, contribute to inflammatory cell recruitment and activation of hepatic fibrogenic cells. Here, we investigated whether macrophage autophagy may protect against chronic liver injury. Experiments were performed in mice with mutations in the autophagy gene Atg5 in the myeloid lineage (Atg5(fl/fl) LysM-Cre mice, referred to as atg5(-/-)) and their wild-type (Atg5(fl/fl), referred to as WT) littermates. Liver fibrosis was induced by repeated intraperitoneal injection of carbon tetrachloride. In vitro studies were performed in cultures or co-cultures of peritoneal macrophages with hepatic myofibroblasts. As compared to WT littermates, atg5(-/-) mice exposed to chronic carbon tetrachloride administration displayed higher hepatic levels of IL1A and IL1B and enhanced inflammatory cell recruitment associated with exacerbated liver injury. In addition, atg5(-/-) mice were more susceptible to liver fibrosis, as shown by enhanced matrix and fibrogenic cell accumulation. Macrophages from atg5(-/-) mice secreted higher levels of reactive oxygen species (ROS)-induced IL1A and IL1B. Moreover, hepatic myofibroblasts exposed to the conditioned medium of macrophages from atg5(-/-) mice showed increased profibrogenic gene expression; this effect was blunted when neutralizing IL1A and IL1B in the conditioned medium of atg5(-/-) macrophages. Finally, administration of recombinant IL1RN (interleukin 1 receptor antagonist) to carbon tetrachloride-exposed atg5(-/-) mice blunted liver injury and fibrosis, identifying IL1A/B as central mediators in the deleterious effects of macrophage autophagy invalidation. These results uncover macrophage autophagy as a novel antiinflammatory pathway regulating liver fibrosis.