Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system.
Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system.
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DOI：
10.1186/s12974-017-0891-9
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发表时间：
2017-06-06
影响因子：
9.3
通讯作者：
Saraiva MJ
中科院分区：
文献类型：
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作者：
Gonçalves NP;Moreira J;Martins D;Vieira P;Obici L;Merlini G;Saraiva M;Saraiva MJ
越来越多的证据支持炎症在家族性淀粉样变性多神经病变（FAP）的神经退行性过程中的关键作用。虽然神经元白细胞介素-1信号通路似乎过度激活，但FAP的免疫反应显然受到损害。因此，在原纤维或原纤维淀粉样蛋白沉积物周围观察到的免疫细胞浸润很少，而这一现象的潜在机制尚不清楚。组织蛋白酶E （CtsE）是抗原呈递和趋化的重要中间体，但其在FAP发病机制中的作用尚不清楚。在本研究中，我们使用小鼠原代巨噬细胞和基于FAP转基因模型和人类样本的体内研究来表征CtsE在不同生理系统中的表达。我们从FAP小鼠模型中发现，CtsE在骨髓源性巨噬细胞中严重减少，可能导致细胞功能损伤。在转基因小鼠的损伤神经中也发现了CtsE水平的降低，最重要的是，在naïve周围神经、感觉神经节、小鼠胃和FAP患者的腓肠神经活检中也发现了CtsE水平的降低。CtsE在组织中的表达与甲状腺转甲状腺素（TTR）沉积有关，并根据所研究的生理系统进行差异调节。用TTR小干扰RNA阻止周围神经系统（PNS）的CtsE沉积。相反，CtsE在脾细胞（主要是单核细胞）或腹腔巨噬细胞中的表达增加，表明巨噬细胞表型不同。总之，我们的数据强调了CtsE作为一种新的FAP生物标志物和先天免疫细胞趋化到疾病最受影响的组织（周围神经和胃肠道）的可能调节剂的潜力。本文的在线版本（doi:10.1186/s12974-017-0891-9）包含补充材料，可供授权用户使用。
Increasing evidence supports a key role for inflammation in the neurodegenerative process of familial amyloidotic polyneuropathy (FAP). While there seems to be an overactivation of the neuronal interleukin-1 signaling pathway, the immune response is apparently compromised in FAP. Accordingly, little immune cell infiltration is observed around pre-fibrillar or fibrillar amyloid deposits, with the underlying mechanism for this phenomenon remaining poorly understood. Cathepsin E (CtsE) is an important intermediate for antigen presentation and chemotaxis, but its role in the pathogenesis of FAP disease remains unknown. In this study, we used both mouse primary macrophages and in vivo studies based on transgenic models of FAP and human samples to characterize CtsE expression in different physiological systems. We show that CtsE is critically decreased in bone marrow-derived macrophages from a FAP mouse model, possibly contributing for cell function impairment. Compromised levels of CtsE were also found in injured nerves of transgenic mice and, most importantly, in naïve peripheral nerves, sensory ganglia, murine stomach, and sural nerve biopsies derived from FAP patients. Expression of CtsE in tissues was associated with transthyretin (TTR) deposition and differentially regulated accordingly with the physiological system under study. Preventing deposition with a TTR small interfering RNA rescued CtsE in the peripheral nervous system (PNS). In contrast, the expression of CtsE increased in splenic cells (mainly monocytes) or peritoneal macrophages, indicating a differential macrophage phenotype. Altogether, our data highlights the potential of CtsE as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease most affected tissues—the peripheral nerve and the gastrointestinal tract. The online version of this article (doi:10.1186/s12974-017-0891-9) contains supplementary material, which is available to authorized users.