Cellular communication network factor 1-stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis.
Cellular communication network factor 1-stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis.
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DOI：
10.1002/hep4.2057
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发表时间：
2022-10
影响因子：
5.1
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中科院分区：
文献类型：
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在肝脏中的炎性损伤之后，中性粒细胞迅速渗入损伤的组织以防御微生物并启动修复过程;这些中性粒细胞寿命短并迅速经历细胞凋亡。肝星状细胞（HSC）是转分化为肌成纤维细胞样细胞的主要前体细胞，其产生大量细胞外基质，促进修复，但如果损伤变为慢性，也可能导致纤维化。基质细胞蛋白质细胞通讯网络因子1（CCN 1）通过结合凋亡细胞中的磷脂酰丝氨酸和吞噬细胞中的整合素αvβ3而作为桥接分子起作用，从而触发凋亡细胞的吞噬作用或吞噬清除。在这里，我们发现CCN 1在四氯化碳（CCl 4）诱导的肝损伤中诱导凋亡中性粒细胞的肝巨噬细胞吞噬，导致活化的转化生长因子（TGF）-β1的产生，进而诱导HSC转分化为肌成纤维细胞样细胞，促进纤维化的发展。因此，在CCN 1中表达单个氨基酸取代的敲入小鼠使其不能结合αvβ3或诱导单核细胞增多症，在中性粒细胞清除、活化TGF-β1的产生和HSC转分化方面受损，导致暴露于CCl 4后肝纤维化大大减少。总结：这些结果揭示了CCN 1在刺激肝巨噬细胞清除凋亡中性粒细胞中的关键作用，这是一个驱动HSC转分化为肌纤维母细胞并成为慢性肝损伤中纤维化的基础的过程。我们发现，CCN 1在CCl 4诱导的肝损伤中诱导肝巨噬细胞凋亡中性粒细胞，导致产生活化的TGF-β1，进而诱导HSC转分化为肌成纤维细胞样细胞，促进纤维化发展。这些结果揭示了CCN 1在刺激肝巨噬细胞清除凋亡中性粒细胞中的关键作用，这是一个驱动HSC转分化为肌纤维母细胞并成为慢性肝损伤中纤维化的基础的过程。
Following inflammatory injury in the liver, neutrophils quickly infiltrate the injured tissue to defend against microbes and initiate the repair process; these neutrophils are short lived and rapidly undergo apoptosis. Hepatic stellate cells (HSCs) are the principal precursor cells that transdifferentiate into myofibroblast‐like cells, which produce a large amount of extracellular matrix that promotes repair but can also lead to fibrosis if the injury becomes chronic. The matricellular protein cellular communication network factor 1 (CCN1) acts as a bridging molecule by binding phosphatidylserine in apoptotic cells and integrin αvβ3 in phagocytes, thereby triggering efferocytosis or phagocytic clearance of the apoptotic cells. Here, we show that CCN1 induces liver macrophage efferocytosis of apoptotic neutrophils in carbon tetrachloride (CCl4)‐induced liver injury, leading to the production of activated transforming growth factor (TGF)‐β1, which in turn induces HSC transdifferentiation into myofibroblast‐like cells that promote fibrosis development. Consequently, knock‐in mice expressing a single amino acid substitution in CCN1 rendering it unable to bind αvβ3 or induce efferocytosis are impaired in neutrophil clearance, production of activated TGF‐β1, and HSC transdifferentiation, resulting in greatly diminished liver fibrosis following exposure to CCl4. Conclusion: These results reveal the crucial role of CCN1 in stimulating liver macrophage clearance of apoptotic neutrophils, a process that drives HSC transdifferentiation into myofibroblastic cells and underlies fibrogenesis in chronic liver injury. We show that CCN1 induces liver macrophage efferocytosis of apoptotic neutrophils in CCl4‐induced liver injury, leading to the production of activated TGF‐β1, which in turn induces HSC transdifferentiation into myofibroblast‐like cells that promote fibrosis development. These results reveal the crucial role of CCN1 in stimulating liver macrophage clearance of apoptotic neutrophils, a process that drives HSC transdifferentiation into myofibroblastic cells and underlies fibrogenesis in chronic liver injury.
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影响因子：
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