CD36 participates in PrP(106-126)-induced activation of microglia.
CD36 participates in PrP(106-126)-induced activation of microglia.
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CD36 参与 PrP106-126 诱导的小胶质细胞激活
DOI：
10.1371/journal.pone.0030756
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhao D
中科院分区：
文献类型：
--
作者：
Kouadir M;Yang L;Tan R;Shi F;Lu Y;Zhang S;Yin X;Zhou X;Zhao D
小胶质细胞活化是朊病毒疾病发病机制的一个特征。朊病毒诱导的小胶质细胞活化的分子机制尚不清楚。在本研究中，我们研究了B类清道夫受体CD36在神经毒性朊蛋白（PrP）片段106-126 （PrP106-126）诱导的小胶质细胞活化中的作用。我们首先检测了暴露于PrP106-126后BV2小胶质细胞中CD36 mRNA表达的时间过程。然后，我们分析了在抗cd36单克隆抗体（mAb）存在或不存在的情况下，prp106 - 126处理的细胞中小胶质细胞活化的不同参数。首先用CD36单克隆抗体阻断CD36受体孵育1小时，然后用神经毒性朊病毒肽PrP106-126处理。结果表明，PrP106-126处理导致CD36 mRNA表达快速但短暂性升高，促炎细胞因子（IL-1β、IL-6和TNF-α） mRNA和蛋白水平上调，iNOS表达和一氧化氮（NO）产生增加，刺激NF-κB和caspase-1的激活，Fyn活性升高。阻断CD36对PrP106-126诱导的NF-κB活化和TNF-α蛋白释放无影响，消除了PrP106-126诱导的iNOS刺激，下调了IL-1β和IL-6 mRNA和蛋白水平的表达以及TNF-α mRNA的表达，降低了no的产生和Fyn的磷酸化，减少了中度PrP106-126处理诱导的caspase-1的裂解，但高浓度PrP106-126处理后对caspase-1的激活无影响。综上所述，这些结果表明CD36参与了PrP106-126诱导的小胶质细胞活化，并且CD36参与PrP106-126与小胶质细胞之间的相互作用可能是通过Src酪氨酸激酶介导的。我们的研究结果为神经毒性朊病毒肽激活小胶质细胞的机制提供了新的见解，并为通过调节CD36信号来治疗朊病毒疾病的新治疗策略开辟了新的视角。
Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106–126 (PrP106–126). We first examined the time course of CD36 mRNA expression upon exposure to PrP106–126 in BV2 microglia. We then analyzed different parameters of microglial activation in PrP106–126-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP106–126. The results showed that PrP106–126 treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP106–126-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP106–126-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP106–126 –treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP106–126. Together, these results suggest that CD36 is involved in PrP106–126-induced microglial activation and that the participation of CD36 in the interaction between PrP106–126 and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling.
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