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首页> 美国卫生研究院文献>Journal of the Boston Society of Medical Sciences >Loss of Discoidin Domain Receptor 2 Promotes Hepatic Fibrosis after Chronic Carbon Tetrachloride through Altered Paracrine Interactions between Hepatic Stellate Cells and Liver-Associated Macrophages
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Loss of Discoidin Domain Receptor 2 Promotes Hepatic Fibrosis after Chronic Carbon Tetrachloride through Altered Paracrine Interactions between Hepatic Stellate Cells and Liver-Associated Macrophages

机译：盘状蛋白域受体2的丢失促进慢性四氯化碳后通过肝星状细胞和肝相关性巨噬细胞之间的旁分泌相互作用改变的肝纤维化。

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摘要

Hepatic stellate cells (HSCs) interact with fibrillar collagen through the discoidin domain receptor 2 (DDR2) in acute hepatic injury, generating increased fibrosis. However, the contribution of DDR2 signaling to chronic liver fibrosis in vivo is unclear, despite its relevance to chronic human liver disease. We administered carbon tetrachloride (CCl4) to DDR2+/+ and DDR2−/− mice twice weekly, and liver tissues and isolated HSCs were analyzed. In contrast to changes seen in acute injury, after chronic CCl4 administration, DDR2−/− livers had increased collagen deposition, gelatinolytic activity, and HSC density. Increased basal gene expression of osteopontin, transforming growth factor-β1, monocyte chemoattractant protein-1, and IL-10 and reduced basal gene expression of matrix metalloproteinase-2, matrix metalloproteinase-13, and collagen type I in quiescent DDR2−/− HSCs were amplified further after chronic CCl4. In concordance, DDR2−/− HSCs isolated from chronically injured livers had enhanced in vitro migration and proliferation, but less extracellular matrix degradative activity. Macrophages from chronic CCl4-treated DDR2−/− livers showed stronger chemoattractive activity toward DDR2−/− HSCs than DDR2+/+ macrophages, increased extracellular matrix degradation, and higher cytokine mRNA expression. In conclusion, loss of DDR2 promotes chronic liver fibrosis after CCl4 injury. The fibrogenic sinusoidal milieu generated in chronic DDR2−/− livers recruits more HSCs to injured regions, which enhances fibrosis. Together, these findings suggest that DDR2 normally orchestrates gene programs and paracrine interactions between HSCs and macrophages that together attenuate chronic hepatic fibrosis.
机译：在急性肝损伤中，肝星状细胞（HSC）通过盘状蛋白结构域受体2（DDR2）与原纤维胶原蛋白相互作用，从而导致纤维化增加。然而，尽管DDR2信号转导与慢性人类肝病有关，但尚不清楚其在体内对慢性肝纤维化的贡献。我们每周两次向DDR2 + / + 和DDR2 -/-小鼠施用四氯化碳（CCl4），并分析肝组织和分离的HSC。与急性损伤中观察到的变化相反，长期施用CCl4后，DDR2 -/-肝脏的胶原蛋白沉积，明胶分解活性和HSC密度增加。静态DDR2中骨桥蛋白，转化生长因子-β1，单核细胞趋化蛋白-1和IL-10的基础基因表达增加，基质金属蛋白酶-2，基质金属蛋白酶-13和I型胶原的基础基因表达降低慢性CCl4后，HSC进一步扩增。一致地，从慢性受伤的肝脏分离的DDR2 -/- HSCs具有增强的体外迁移和增殖能力，但细胞外基质降解活性较低。慢性CCl4处理的DDR2 -/-肝脏的巨噬细胞对DDR2 -/- HSC的化学吸引活性比 DDR2 + / + 巨噬细胞，细胞外基质降解增加和细胞因子mRNA表达升高。总之，DDR2的丢失促进CCl4损伤后的慢性肝纤维化。慢性 DDR2 -/- 肝脏中产生的纤维化正弦曲线环境将更多的HSC募集到受伤区域，从而增强了纤维化。总之，这些发现表明，DDR2正常协调HSC与巨噬细胞之间的基因程序和旁分泌相互作用，共同减弱慢性肝纤维化。

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