TLR4 promotes Cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis.
TLR4 promotes Cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis.
复制标题
DOI：
10.1645/ge-2703.1
复制
发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
LaRusso NF
中科院分区：
文献类型：
--
作者：
O'Hara SP;Bogert PS;Trussoni CE;Chen X;LaRusso NF
胆管细胞是肝内胆管的上皮细胞，表达多种Toll样受体（TLR），因此具有识别和响应微生物病原体的能力。在以前的工作中，我们证明了TLR 4，这是由革兰氏阴性脂多糖（LPS）激活，上调胆管细胞在体外感染隐孢子虫，并有助于NF κ B激活。在此，我们利用胆源性隐孢子虫病的体内模型，阐明了TLR 4在C.寄生虫感染动力学和肝胆病理生理学。我们观察到C57 BL小鼠在感染后三周清除了感染。相反，在感染后4周，TLR 4缺陷小鼠的胆汁和粪便中检测到寄生虫。肝酶、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）以及促炎细胞因子肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白细胞介素（IL）-6在感染后1 - 2周达到峰值，并在感染后4周恢复正常。C57 BL小鼠在感染后一周也表现出增加的胆管细胞增殖（PCNA染色），其在感染后两周解决。相比之下，TLR 4缺陷型小鼠在感染后4周内表现出持续升高的血清ALT和AST，升高的肝脏IL-6水平，以及肝细胞坏死的组织学证据，增加的炎性细胞浸润和胆管细胞增殖。这些数据表明，TLR 4介导的反应是有效根除胆源性丙型肝炎所必需的。在体内，这种模式识别受体的缺乏导致炎症反应的改变和肝胆病理学的增加。
Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, express multiple toll-like receptors (TLRs) and thus have the capacity to recognize and respond to microbial pathogens. In previous work we demonstrated that TLR4, which is activated by gram-negative lipopolysaccharide (LPS), is upregulated in cholangiocytes in response to infection with Cryptosporidium parvum in vitro and contributes to NFkB activation. Here, using an in vivo model of biliary cryptosporidiosis we addressed the functional role of TLR4 in C. parvum infection dynamics and hepatobiliary pathophysiology. We observed that C57BL mice clear the infection by three weeks post-infection. In contrast, parasites were detected in bile and stool in TLR4 deficient mice at four weeks post-infection. The liver enzymes, alanine transaminase (ALT) and aspartate transaminase (AST), and the proinflammatory cytokines Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-γ, and Interleukin (IL)-6 peaked at one to two weeks postinfection and normalized by four weeks in infected C57BL mice. C57BL mice also demonstrated increased cholangiocyte proliferation (PCNA staining) at one-week post-infection, which was resolved by two weeks post-infection. In contrast, TLR4 deficient mice showed persistently elevated serum ALT and AST, elevated hepatic IL-6 levels, and histological evidence of hepatocyte necrosis, increased inflammatory cell infiltration, and cholangiocyte proliferation through four weeks post-infection. These data suggest that a TLR4-mediated response is required for efficient eradication of biliary C. parvum infection in vivo, and lack of this pattern recognition receptor contributes to an altered inflammatory response and an increase in hepatobiliary pathology.