Schistosome egg antigen stimulates the secretion of miR-33-carrying extracellular vesicles from macrophages to promote hepatic stellate cell activation and liver fibrosis in schistosomiasis.
Schistosome egg antigen stimulates the secretion of miR-33-carrying extracellular vesicles from macrophages to promote hepatic stellate cell activation and liver fibrosis in schistosomiasis.
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DOI：
10.1371/journal.pntd.0011385
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发表时间：
2023-05
影响因子：
3.8
通讯作者：
Su, Chuan
中科院分区：
文献类型：
--
作者：
Qi, Xin;Pu, Yanan;Chen, Fanyan;Dong, Liyang;Ma, Yongbin;Wang, Junling;Yin, Guo;Lu, Di;Chen, Xiaojun;Zhu, Jifeng;Li, Yalin;Zhou, Sha;Su, Chuan
血吸虫病是热带和亚热带国家中一种严重且被忽视的疾病。由日本血吸虫（S. japonicum）或曼氏血吸虫（S. mansoni）感染引起的肝血吸虫病的主要病理是鸡蛋诱导的肉芽肿和随后的肝脏纤维化。肝星状细胞（hsc）的激活是肝纤维化的主要驱动因素。巨噬细胞（Mφ）占肝肉芽肿细胞的30%，通过分泌细胞因子或趋化因子，直接或间接地通过旁分泌机制调节HSC的活化。目前，m φ衍生的细胞外囊泡（EVs）广泛参与细胞与邻近细胞群的通讯。然而，在血吸虫感染过程中，m φ衍生的ev是否能够靶向邻近的hsc来调节其激活，这在很大程度上仍是未知的。血吸虫卵抗原（Schistosome egg antigen， SEA）被认为是肝脏病理的主要致病复合体。在这里，我们证明SEA诱导Mφ产生大量的细胞外囊泡，这些囊泡通过激活hsc的自分泌TGF-β1信号直接激活hsc。机制上，sea刺激的Mφ衍生的EVs含有升高的miR-33， miR-33被转移到HSC中，随后通过靶向和下调SOCS3表达上调HSC中自分泌TGF-β1，从而促进HSC活化。最后，我们验证了sea刺激的Mφ衍生的ev利用封闭的miR-33促进日本血吸虫感染小鼠的HSC激活和肝纤维化。总之，我们的研究表明，在肝血吸虫病进展过程中，m φ衍生的ev在hsc的旁分泌调节中发挥了重要作用，代表了预防肝血吸虫病肝纤维化的潜在靶点。血吸虫病是一种被忽视的寄生虫病，影响着热带和亚热带地区2.5亿多人。在常见的致病种中，日本血吸虫和曼氏血吸虫主要引起肝脏血吸虫病，主要是由于血吸虫虫卵滞留肝脏，导致肉芽肿性炎症和肝纤维化。肝性血吸虫病期间肝纤维化的主要驱动因素是肝组织造血干细胞的活化。巨噬细胞（Mφ）与HSC活性密切相关。目前，许多证据支持m φ衍生的细胞外囊泡（EVs）的关键作用。然而，m φ衍生的ev在肝血吸虫病中参与HSC通讯和调节的可能性仍然很大程度上未知。在这项研究中，作者证明日本血吸虫感染利用m φ衍生的ev促进HSC活化和肝纤维化。简而言之，血吸虫卵抗原（SEA）诱导Mφ分泌大量富集mir -33的ev，这些ev通过靶向HSC中的SOCS3转移到自分泌TGF-β1的产生，从而促进HSC活化和肝纤维化。这些发现提供了一个以前未被认识到的基于m - φ- ev的HSC激活治疗靶点，它可以被操纵来预防肝血吸虫病期间的肝纤维化。
Schistosomiasis is a serious and neglected disease with a high prevalence in tropical and subtropical countries. The primary pathology of hepatic schistosomiasis caused by Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S. mansoni) infection is egg-induced granuloma and subsequent fibrosis in the liver. Activation of hepatic stellate cells (HSCs) is the central driver of liver fibrosis. Macrophages (Mφ), making up 30% of cells in hepatic granulomas, directly or indirectly regulate HSC activation by paracrine mechanisms, via secreting cytokines or chemokines. Currently, Mφ-derived extracellular vesicles (EVs) are broadly involved in cell communication with adjacent cell populations. However, whether Mφ-derived EVs could target neighboring HSCs to regulate their activation during schistosome infection remains largely unknown. Schistosome egg antigen (SEA) is considered to be the main pathogenic complex mixture involved in liver pathology. Here, we demonstrated that SEA induced Mφ to produce abundant extracellular vesicles, which directly activated HSCs by activating their autocrine TGF-β1 signaling. Mechanistically, EVs derived from SEA-stimulated Mφ contained increased miR-33, which were transferred into HSCs and subsequently upregulated autocrine TGF-β1 in HSCs through targeting and downregulating SOCS3 expression, thereby promoting HSC activation. Finally, we validated that EVs derived from SEA-stimulated Mφ utilized enclosed miR-33 to promote HSC activation and liver fibrosis in S. japonicum-infected mice. Overall, our study indicates that Mφ-derived EVs play important roles in the paracrine regulation of HSCs during the progression of hepatic schistosomiasis, representing a potential target for the prevention of liver fibrosis in hepatic schistosomiasis. Schistosomiasis is a neglected parasitic disease affecting over 250 million people in tropical and subtropical regions. Among the common pathogenic species, Schistosoma japonicum and Schistosoma mansoni mainly cause hepatic schistosomiasis, which is mainly attributed to liver-trapped schistosome eggs, leading to granulomatous inflammation and liver fibrosis. HSC activation is the central driver of liver fibrosis during hepatic schistosomiasis. Macrophages (Mφ) are tightly connected to HSC activity. Currently, much evidence supports the pivotal role of Mφ-derived extracellular vesicles (EVs). However, the potential involvement of Mφ-derived EVs in HSC communication and modulation in hepatic schistosomiasis remains largely unknown. In this study, the authors illustrate that S. japonicum infection utilizes Mφ-derived EVs to promote HSC activation and liver fibrosis. Briefly, schistosome egg antigen (SEA) induces Mφ to secrete abundant miR-33-enriched EVs, which are transferred to enhance autocrine TGF-β1 production by targeting SOCS3 in HSCs, thereby promoting HSC activation and liver fibrosis. These discoveries provide a previously unrecognized Mφ-EVs-based therapeutic target regarding HSC activation, which can be manipulated to prevent liver fibrosis during hepatic schistosomiasis.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.1038/nri3622
发表时间：
2014-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.4
作者：
Barron, Luke;Wynn, Thomas A.
通讯作者：
Wynn, Thomas A.
重组腺相关病毒介导的 microRNA-21 抑制通过抑制 IL-13 和转化生长因子 β 1 途径保护小鼠免受致命的血吸虫感染
影响因子：
13.5
作者：
He, Xing;Xie, Jun;Zhang, Dongmei;Su, Qin;Sai, Xue;Bai, Ruipu;Chen, Chao;Luo, Xufeng;Gao, Guangping;Pan, Weiqing
通讯作者：
Pan, Weiqing
人脐带间充质干细胞来源的细胞外囊泡通过转移 miR-410 促进肺腺癌生长。
影响因子：
9
作者：
Dong L;Pu Y;Zhang L;Qi Q;Xu L;Li W;Wei C;Wang X;Zhou S;Zhu J;Wang X;Liu F;Chen X;Su C
通讯作者：
Su C