Abstract

Background

Systemic amyloidosis refers to a group of protein misfolding disorders characterized by the extracellular deposition of amyloid fibrils in organs and tissues. For reasons heretofore unknown, amyloid deposits are not recognized by the immune system, and progressive deposition leads to organ dysfunction.

Methods

In vitro and in vivo phagocytosis assays were performed to elucidate the impact of collagen and other amyloid associated proteins (eg serum amyloid p component and apolipoprotein E) had on amyloid phagocytosis. Immunohistochemical and histopathological staining regimens were employed to analyze collagen-amyloid interactions and immune responses.

Results

Histological analysis of amyloid-laden tissue indicated that collagen is intimately associated with amyloid deposits. We report that collagen inhibits phagocytosis of amyloid fibrils by macrophages. Treatment of 15 patient-derived amyloid extracts with collagenase significantly enhanced amyloid phagocytosis. Preclinical mouse studies indicated that collagenase treatment of amyloid extracts significantly enhanced clearance as compared to controls, coincident with increased immune cell infiltration of the subcutaneous amyloid lesion.

Conclusions

These data suggest that amyloid-associated collagen serves as a ‘don’t eat me’ signal, thereby hindering clearance of amyloid. Targeted degradation of amyloid-associated collagen could result in innate immune cell recognition and clearance of pathologic amyloid deposits.

中文翻译：

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胶原蛋白在体外和体内抑制淀粉样蛋白的吞噬作用，并可能充当“不要吃我”的信号

摘要

背景

系统性淀粉样变性是指一组以淀粉样原纤维在器官和组织中沉积为特征的蛋白质错误折叠疾病。由于迄今为止未知的原因，淀粉样蛋白沉积物不被免疫系统识别，并且进行性沉积导致器官功能障碍。

方法

进行体外和体内吞噬试验以阐明胶原蛋白和其他淀粉样蛋白相关蛋白（例如血清淀粉样蛋白p成分和载脂蛋白E）对淀粉样蛋白吞噬作用的影响。采用免疫组织化学和组织病理学染色方案来分析胶原蛋白-淀粉样蛋白相互作用和免疫反应。

结果

富含淀粉样蛋白的组织的组织学分析表明胶原蛋白与淀粉样蛋白沉积密切相关。我们报告胶原蛋白抑制巨噬细胞对淀粉样原纤维的吞噬作用。用胶原酶处理 15 名患者来源的淀粉样蛋白提取物显着增强了淀粉样蛋白的吞噬作用。临床前小鼠研究表明，与对照相比，淀粉样蛋白提取物的胶原酶处理显着增强了清除率，这与皮下淀粉样蛋白病变的免疫细胞浸润增加相一致。

结论

这些数据表明，淀粉样蛋白相关的胶原蛋白充当“不要吃我”的信号，从而阻碍淀粉样蛋白的清除。淀粉样蛋白相关胶原蛋白的靶向降解可能导致先天免疫细胞识别和清除病理性淀粉样蛋白沉积物。