C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages.
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages.
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C5a 激活人戈谢 iPSC 衍生巨噬细胞中的促炎基因表达谱。
DOI：
10.3390/ijms22189912
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发表时间：
2021-09-14
影响因子：
5.6
通讯作者：
Feldman RA
中科院分区：
文献类型：
--
作者：
Serfecz JC;Saadin A;Santiago CP;Zhang Y;Bentzen SM;Vogel SN;Feldman RA
戈谢病 (GD) 是一种常染色体隐性遗传病，由双等位基因 GBA1 突变引起，该突变会降低溶酶体酶 β-葡萄糖脑苷脂酶 (GCase) 的活性。 GCase 催化葡萄糖神经酰胺 (GluCer)（一种普遍存在的鞘糖脂）转化为葡萄糖和神经酰胺。 GCase 缺乏会导致 GluCer 及其代谢物葡萄糖基鞘氨醇 (GluSph) 在许多组织和器官中积累。在免疫系统中，GCase 缺乏会导致信号转导事件失调，从而导致炎症环境。众所周知，补体系统会促进炎症，补体抑制剂目前被认为是治疗 GD 的新疗法；然而，补体驱动系统性巨噬细胞介导的炎症的机制仍不完全清楚。为了帮助理解所涉及的机制，我们使用了人类 GD 诱导的多能干细胞 (iPSC) 衍生的巨噬细胞。我们发现，GD 巨噬细胞通过补体成分 C5a (C5aR1) 受体 1 介导的先天免疫反应，表现出炎症细胞因子的加剧。定量 RT-PCR 和 ELISA 测定表明，在重组 C5a (rC5a) 存在的情况下，GD 巨噬细胞分泌的 TNF-α 水平比 rC5a 刺激的对照巨噬细胞高 8-10 倍。 PMX53 是一种 C5aR1 阻断剂，可逆转 GD 巨噬细胞 TNF-α 的产生增强，表明观察到的效应主要是 C5aR1 介导的。为了进一步分析 rC5a 刺激引起的变化程度，我们对 rC5a 处理的巨噬细胞转录组进行了基因阵列分析。我们发现，与 rC5a 刺激的对照相比，rC5a 刺激的 GD 巨噬细胞表现出与 TNF-α 炎症反应相关的基因表达增加。我们的结果表明，rC5a 诱导的 GD 巨噬细胞炎症会激活独特的免疫反应，支持 C5a-C5aR1 受体轴抑制剂的潜在用途，以减轻与 GD 相关的慢性炎症异常。
Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.
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DOI：
10.4061/2011/216298
发表时间：
2011
期刊：
Parkinson's disease
影响因子：
--
作者：
Flood PM;Qian L;Peterson LJ;Zhang F;Shi JS;Gao HM;Hong JS
通讯作者：
Hong JS
影响因子：
168.9
作者：
CERUTTI, PA
通讯作者：
CERUTTI, PA
影响因子：
6
作者：
Akiyama T;Sato S;Ko SBH;Sano O;Sato S;Saito M;Nagai H;Ko MSH;Iwata H
通讯作者：
Iwata H
影响因子：
7.8
作者：
Aflaki E;Moaven N;Borger DK;Lopez G;Westbroek W;Chae JJ;Marugan J;Patnaik S;Maniwang E;Gonzalez AN;Sidransky E
通讯作者：
Sidransky E
影响因子：
3.7
作者：
Kitatani, Kazuyuki;Wada, Masayuki;Hannun, Yusuf A.
通讯作者：
Hannun, Yusuf A.