CCR2 and CD44 promote inflammatory cell recruitment during fatty liver formation in a lithogenic diet fed mouse model.
CCR2 and CD44 promote inflammatory cell recruitment during fatty liver formation in a lithogenic diet fed mouse model.
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DOI：
10.1371/journal.pone.0065247
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Maurer KJ
中科院分区：
文献类型：
--
作者：
Egan CE;Daugherity EK;Rogers AB;Abi Abdallah DS;Denkers EY;Maurer KJ
非酒精性脂肪性肝病（NAFLD）是一种常见的疾病，具有一系列表现。目前的研究利用了NAFLD的致石饮食模型。将饲料喂给对肝炎具有抗性（AKR）或易感性（BALB/c和C57 BL/6）的小鼠，然后进行分子和流式细胞术分析。在此之后，在免疫基因中具有特定突变的同类小鼠中采取了类似的方法。最初的研究发现，在易感的C57 BL/6（B6）小鼠中，趋化因子受体CCR 2的多种配体显著而深刻地增加，CD 44表达增加，但耐药的AKR小鼠则没有。Ccr 2 −/−小鼠完全免受肝炎的影响，Cd 44 −/−小鼠部分受到保护。尽管可以防止炎症，但两种菌株均表现出相似的组织学脂肪变性评分和血清肝酶显着增加。在饮食喂养的B6小鼠中，CD 45 + CD 44+细胞与透明质酸（HA）结合，但不与Cd 44 −/−或Ccr 2 −/−小鼠结合。Ccr 2 −/−小鼠表现出减少的HA结合表型，尤其是在单核细胞和CD 8 + T细胞中。总之，本研究表明，CCR 2完全和CD 44的缺乏部分减少肝白细胞募集。这些数据还提供了证据表明，在肝脂质蓄积期间产生了多种冗余的CCR 2配体，并描述了在来自易感菌株的某些白细胞亚群中响应LD喂养诱导强HA结合表型。
Non-alcoholic fatty liver disease (NAFLD) is a common disease with a spectrum of presentations. The current study utilized a lithogenic diet model of NAFLD. The diet was fed to mice that are either resistant (AKR) or susceptible (BALB/c and C57BL/6) to hepatitis followed by molecular and flow cytometric analysis. Following this, a similar approach was taken in congenic mice with specific mutations in immunological genes. The initial study identified a significant and profound increase in multiple ligands for the chemokine receptor CCR2 and an increase in CD44 expression in susceptible C57BL/6 (B6) but not resistant AKR mice. Ccr2−/− mice were completely protected from hepatitis and Cd44−/− mice were partially protected. Despite protection from inflammation, both strains displayed similar histological steatosis scores and significant increases in serum liver enzymes. CD45+CD44+ cells bound to hyaluronic acid (HA) in diet fed B6 mice but not Cd44−/− or Ccr2−/− mice. Ccr2−/− mice displayed a diminished HA binding phenotype most notably in monocytes, and CD8+ T-cells. In conclusion, this study demonstrates that absence of CCR2 completely and CD44 partially reduces hepatic leukocyte recruitment. These data also provide evidence that there are multiple redundant CCR2 ligands produced during hepatic lipid accumulation and describes the induction of a strong HA binding phenotype in response to LD feeding in some subsets of leukocytes from susceptible strains.
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