Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis.
Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis.
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DOI：
10.1042/cs20110515
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发表时间：
2012-10
期刊：
影响因子：
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通讯作者：
Marra F
中科院分区：
文献类型：
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作者：
Galastri S;Zamara E;Milani S;Novo E;Provenzano A;Delogu W;Vizzutti F;Sutti S;Locatelli I;Navari N;Vivoli E;Caligiuri A;Pinzani M;Albano E;Parola M;Marra F
CCL 2（CC趋化因子配体2）（或单核细胞趋化蛋白-1）的表达调节肝脏和脂肪组织中的炎性细胞浸润，促进脂肪变性。然而，其在脂肪性肝炎发病机制中的作用仍不确定。在本研究中，我们研究了在两种不同遗传背景（即Balb/C和C57/Bl 6 J）的缺乏CCL 2基因的小鼠中由MCD饮食（蛋氨酸/胆碱缺乏饮食）诱导的非酒精性脂肪性肝炎的发生。WT（野生型）和CCL 2-KO（基因敲除）小鼠喂食富含脂质的MCD饲料或对照饲料8周。在喂食MCD饲料的Balb/C小鼠中，CCL 2的缺乏与ALT（丙氨酸氨基转移酶）水平较低、炎症细胞浸润减少以及氧化应激相关产物的产生减少有关。天狼星红染色显示3区中的细胞周纤维化，图像分析显示CCL 2-KO小鼠中显著较低的基质积累。这与TGF-β（转化生长因子-β）、I型前胶原、TIMP-1（金属蛋白酶组织抑制剂-1）和α-平滑肌肌动蛋白的肝脏表达减少有关。相比之下，在C57 Bl/6背景的小鼠中，与喂食MCD饲料的WT和CCL 2-KO动物相比，ALT水平、炎症或纤维化均无显著差异。与此一致的是，与纤维化相关的基因在两组动物中的表达水平相当。对参与炎症和修复的几种基因表达的比较表明，IL（白细胞介素）-4和M2标记物MGL-1（巨噬细胞半乳糖型C型凝集素1）在Balb/C和C57 Bl/6小鼠中差异表达。在喂食MCD饲料的所有小鼠组中均未观察到脂肪变性程度的显著差异。我们的结论是，在实验性小鼠脂肪性肝炎，CCL 2缺乏症的影响显着依赖于遗传背景。
Expression of CCL2 (CC chemokine ligand 2) (or monocyte chemoattractant protein-1) regulates inflammatory cell infiltration in the liver and adipose tissue, favouring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In the present study, we investigated the development of non-alcoholic steatohepatitis induced by an MCD diet (methionine/choline-deficient diet) in mice lacking the CCL2 gene on two different genetic backgrounds, namely Balb/C and C57/Bl6J. WT (wild-type) and CCL2-KO (knockout) mice were fed on a lipid-enriched MCD diet or a control diet for 8 weeks. In Balb/C mice fed on the MCD diet, a lack of CCL2 was associated with lower ALT (alanine transaminase) levels and reduced infiltration of inflammatory cells, together with a lower generation of oxidative-stress-related products. Sirius Red staining demonstrated pericellular fibrosis in zone 3, and image analysis showed a significantly lower matrix accumulation in CCL2-KO mice. This was associated with reduced hepatic expression of TGF-β (transforming growth factor-β), type I procollagen, TIMP-1 (tissue inhibitor of metalloproteinases-1) and α-smooth muscle actin. In contrast, in mice on a C57Bl/6 background, neither ALT levels nor inflammation or fibrosis were significantly different comparing WT and CCL2-KO animals fed on an MCD diet. In agreement, genes related to fibrogenesis were expressed to comparable levels in the two groups of animals. Comparison of the expression of several genes involved in inflammation and repair demonstrated that IL (interleukin)-4 and the M2 marker MGL-1 (macrophage galactose-type C-type lectin 1) were differentially expressed in Balb/C and C57Bl/6 mice. No significant differences in the degree of steatosis were observed in all groups of mice fed on the MCD diet. We conclude that, in experimental murine steatohepatitis, the effects of CCL2 deficiency are markedly dependent on the genetic background.