Absence of CD14 delays progression of prion diseases accompanied by increased microglial activation.
Absence of CD14 delays progression of prion diseases accompanied by increased microglial activation.
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CD14 的缺失会延迟朊病毒疾病的进展，并伴有小胶质细胞激活的增加。
DOI：
10.1128/jvi.02072-13
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Horiuchi M.
中科院分区：
文献类型：
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作者：
Sakai K;Hasebe R;Takahashi Y;Song CH;Suzuki A;Yamasaki T;Horiuchi M.
朊病毒病是一种致命的神经退行性疾病，其特征在于PrPSc的积聚、神经元和神经胶质细胞的空泡化、星形细胞增多和小胶质细胞活化。在感染朊病毒的小鼠脑中观察到先天免疫相关因子（包括补体因子和CD 14）的基因表达上调，即使在感染的早期阶段。当CD 14敲除（CD 14 −/−）小鼠脑内感染钱德勒和带广朊病毒株时，小鼠存活时间长于野生型（WT）小鼠，表明CD 14影响朊病毒疾病的进展。免疫荧光染色可以区分正常的朊蛋白和疾病特异性形式的朊蛋白（PrPSc），结果显示，与WT小鼠相比，CD 14 −/−小鼠中PrPSc的沉积延迟到感染的中期。免疫组织化学染色Iba 1，一种活化小胶质细胞的标记物，显示与WT小鼠相比，朊病毒感染的CD 14 −/−小鼠中的小胶质细胞活化增加。有趣的是，伴随着小胶质细胞活化的增加，抗炎细胞因子白细胞介素-10（IL-10）和转化生长因子β（TGF-β）似乎在朊病毒感染的CD 14 −/−小鼠中更早表达。相比之下，在感染的早期阶段，CD 14 −/−小鼠中的IL-1β表达似乎减少。双重免疫荧光染色显示，CD 11b和Iba 1阳性的小胶质细胞主要产生抗炎细胞因子，表明CD 14 −/−小鼠中的小胶质细胞在感染早期具有抗炎状态。这些结果表明，CD 14通过在感染早期抑制脑中的抗炎反应在疾病进展中起作用。
Prion diseases are fatal neurodegenerative disorders characterized by accumulation of PrPSc, vacuolation of neurons and neuropil, astrocytosis, and microglial activation. Upregulation of gene expressions of innate immunity-related factors, including complement factors and CD14, is observed in the brains of mice infected with prions even in the early stage of infections. When CD14 knockout (CD14−/−) mice were infected intracerebrally with the Chandler and Obihiro prion strains, the mice survived longer than wild-type (WT) mice, suggesting that CD14 influences the progression of the prion disease. Immunofluorescence staining that can distinguish normal prion protein from the disease-specific form of prion protein (PrPSc) revealed that deposition of PrPScwas delayed in CD14−/−mice compared with WT mice by the middle stage of the infection. Immunohistochemical staining with Iba1, a marker for activated microglia, showed an increased microglial activation in prion-infected CD14−/−mice compared to WT mice. Interestingly, accompanied by the increased microglial activation, anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor β (TGF-β) appeared to be expressed earlier in prion-infected CD14−/−mice. In contrast, IL-1β expression appeared to be reduced in the CD14−/−mice in the early stage of infection. Double immunofluorescence staining demonstrated that CD11b- and Iba1-positive microglia mainly produced the anti-inflammatory cytokines, suggesting anti-inflammatory status of microglia in the CD14−/−mice in the early stage of infection. These results imply that CD14 plays a role in the disease progression by suppressing anti-inflammatory responses in the brain in the early stage of infection.