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.
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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DOI：
10.1016/j.ajpath.2011.09.002
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发表时间：
2011-12
期刊：
影响因子：
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通讯作者：
E. Olaso;B. Arteta;Aitor Benedicto;Olatz Crende;S. Friedman
中科院分区：
文献类型：
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作者：
E. Olaso;B. Arteta;Aitor Benedicto;Olatz Crende;S. Friedman
在急性肝损伤中，肝星状细胞（HSC）通过盘状结构域受体2（DDR2）与纤维状胶原相互作用，产生增加的纤维化。然而，DDR2信号传导对体内慢性肝纤维化的贡献尚不清楚，尽管其与慢性人类肝病相关。我们每周两次给DDR2 +/+和DDR2 −/−小鼠注射四氯化碳（CCl 4），分析肝组织和分离的HSC。与急性损伤中观察到的变化相反，慢性CCl 4给药后，DDR2−/−肝脏的胶原沉积、明胶分解活性和HSC密度增加。慢性CCl 4处理后，静止期DDR2 −/− HSC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减少。一致的是，从慢性损伤的肝脏中分离的DDR2−/− HSC在体外迁移和增殖增强，但细胞外基质降解活性较低。慢性CCl 4处理的DDR2 −/−肝脏巨噬细胞对DDR2 −/− HSC的化学吸引活性强于DDR2 +/+巨噬细胞，细胞外基质降解增加，细胞因子mRNA表达增加。总之，DDR2的缺失会促进CCl 4损伤后的慢性肝纤维化。慢性DDR2 −/−肝脏中产生的纤维化正弦环境将更多的HSC招募到损伤区域，从而增强纤维化。总之，这些发现表明DDR2通常协调HSC和巨噬细胞之间的基因程序和旁分泌相互作用，共同减轻慢性肝纤维化。
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 fibrosisin vivois unclear, despite its relevance to chronic human liver disease. We administered carbon tetrachloride (CCl4) toDDR2+/+andDDR2−/−mice twice weekly, and liver tissues and isolated HSCs were analyzed. In contrast to changes seen in acute injury, after chronic CCl4administration,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 quiescentDDR2−/−HSCs were amplified further after chronic CCl4. In concordance,DDR2−/−HSCs isolated from chronically injured livers had enhancedin vitromigration and proliferation, but less extracellular matrix degradative activity. Macrophages from chronic CCl4-treatedDDR2−/−livers showed stronger chemoattractive activity towardDDR2−/−HSCs thanDDR2+/+macrophages, increased extracellular matrix degradation, and higher cytokine mRNA expression. In conclusion, loss of DDR2 promotes chronic liver fibrosis after CCl4injury. The fibrogenic sinusoidal milieu generated in chronicDDR2−/−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.