Methylated BSA mimics amyloid-related proteins and triggers inflammation.
Methylated BSA mimics amyloid-related proteins and triggers inflammation.
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甲基化的BSA模拟淀粉样蛋白相关蛋白和触发炎症。
DOI：
10.1371/journal.pone.0063214
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cao W
中科院分区：
文献类型：
--
作者：
Di Domizio J;Dorta-Estremera S;Cao W
炎症或自身免疫性疾病的机制研究需要生成能够再现在患者中观察到的免疫反应改变的小鼠模型。甲基化牛血清白蛋白（Methylated bovine serum albumin, mBSA）已被广泛用于在体内诱导抗原特异性器官炎症或与单链DNA （single - strand DNA, ssDNA）结合产生抗核酸抗体。然而，这种修饰蛋白引发炎症的机制尚不清楚。通过分析mBSA的生化特性，我们发现mBSA具有蛋白质错误折叠途径中间体的特征。mBSA很容易与一系列对淀粉样蛋白原纤维具有结合特异性的染料相互作用。有趣的是，mBSA显示出细胞毒性活性，其与ssDNA的结合进一步促进了富含β -sheet的淀粉样蛋白原纤维的形成。此外，mBSA被血清淀粉样蛋白P识别，这是一种与体内淀粉样斑块一致相关的蛋白质。在巨噬细胞中，我们观察到mBSA破坏溶酶体腔室，沿NLRP3炎症体通路发出信号，并激活caspase 1，从而导致IL-1β的产生。在体内，mBSA触发了依赖于IL-1β诱导的快速和显著的免疫细胞浸润。综上所述，这些数据表明，通过模拟淀粉样蛋白，mBSA表现出强大的先天免疫功能，并作为一种有效的佐剂。这些发现促进了我们对异常免疫反应如何导致自身免疫反应的潜在机制的理解。
The mechanistic study of inflammatory or autoimmune diseases requires the generation of mouse models that reproduce the alterations in immune responses observed in patients. Methylated bovine serum albumin (mBSA) has been widely used to induce antigen-specific inflammation in targeted organs or in combination with single stranded DNA (ssDNA) to generate anti-nucleic acids antibodies in vivo. However, the mechanism by which this modified protein triggers inflammation is poorly understood. By analyzing the biochemical properties of mBSA, we found that mBSA exhibits features of an intermediate of protein misfolding pathway. mBSA readily interact with a list of dyes that have binding specificity towards amyloid fibrils. Intriguingly, mBSA displayed cytotoxic activity and its binding to ssDNA further enhanced formation of beta-sheet rich amyloid fibrils. Moreover, mBSA is recognized by the serum amyloid P, a protein unanimously associated with amyloid plaques in vivo. In macrophages, we observed that mBSA disrupted the lysosomal compartment, signaled along the NLRP3 inflammasome pathway, and activated caspase 1, which led to the production of IL-1β. In vivo, mBSA triggered rapid and prominent immune cell infiltration that is dependent on IL-1β induction. Taken together, these data demonstrate that by mimicking amyloidogenic proteins mBSA exhibits strong innate immune functions and serves as a potent adjuvant. These findings advance our understanding on the underlying mechanism of how aberrant immune responses lead to autoimmune reactions.
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影响因子：
3.7
作者：
Hawe, Andrea;Sutter, Marc;Jiskoot, Wim
通讯作者：
Jiskoot, Wim
DOI：
10.1073/pnas.1206923109
发表时间：
2012-09-04
影响因子：
11.1
作者：
Di Domizio, Jeremy;Dorta-Estremera, Stephanie;Cao, Wei
通讯作者：
Cao, Wei
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1016/0090-1229(89)90034-2
发表时间：
1989-06-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
GILKESON, GS;GRUDIER, JP;PISETSKY, DS
通讯作者：
PISETSKY, DS
影响因子：
30.5
作者：
通讯作者：
--