Skeletal myotube-derived extracellular vesicles enhance itaconate production and attenuate inflammatory responses of macrophages.
Skeletal myotube-derived extracellular vesicles enhance itaconate production and attenuate inflammatory responses of macrophages.
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DOI：
10.3389/fimmu.2023.1099799
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发表时间：
2023
影响因子：
7.3
通讯作者：
Yuan, Zhi-Min
中科院分区：
文献类型：
--
作者：
Yamaguchi, Atomu;Maeshige, Noriaki;Yan, Jiawei;Ma, Xiaoqi;Uemura, Mikiko;Matsuda, Mami;Nishimura, Yuya;Hasunuma, Tomohisa;Kondo, Hiroyo;Fujino, Hidemi;Yuan, Zhi-Min
巨噬细胞在先天免疫中起着重要作用。虽然巨噬细胞炎症是生物防御所必需的，但必须适当控制。细胞外囊泡（EVs）是从所有类型的细胞中释放出来的小囊泡，在细胞间通讯中起着核心作用。骨骼肌被认为可以释放抗炎因子，但肌管源性ev对巨噬细胞的影响尚不清楚。作为巨噬细胞的抗炎机制，免疫应答基因1 (IRG1)-衣康酸通路是必不可少的。在这项研究中，我们发现骨骼肌源性ev抑制巨噬细胞炎症反应，上调IRG1-itaconate通路。将C2C12成肌细胞分化成肌管，用超离心法提取ev。将骨骼肌管来源的ev给予小鼠骨髓来源的巨噬细胞，然后进行脂多糖（LPS）刺激，并通过RT-qPCR检测炎症细胞因子的表达。采用CE/MS检测加入ev后巨噬细胞代谢产物丰度，RT-PCR检测IRG1表达。此外，对EV处理后的巨噬细胞进行RNA-seq分析。EVs可减弱lps诱导的巨噬细胞促炎因子的表达。在ev处理组，衣康酸丰度和IRG1表达显著升高。RNA-seq分析显示，EV处理后巨噬细胞中PI3K-Akt和JAK-STAT通路被激活。肌管EVs中最丰富的miRNA是miR-206-3p，其次是miR-378a-3p、miR-30d-5p和miR-21a-5p。骨骼肌管EVs可能通过上调IRG1表达来增加衣康酸的产生，并在巨噬细胞中表现出抗炎作用。这种抗炎作用可能涉及PI3K-Akt和JAK-STAT通路。EVs内的miRNA谱暗示miR-206-3p、miR-378a-3p、miR-30d-5p和miR-21a-5p可能与EVs的抗炎作用有关。总之，在本研究中，我们发现肌管来源的EVs通过激活IRG1-itaconate通路来阻止巨噬细胞的炎症反应。
Macrophages play an important role in the innate immunity. While macrophage inflammation is necessary for biological defense, it must be appropriately controlled. Extracellular vesicles (EVs) are small vesicles released from all types of cells and play a central role in intercellular communication. Skeletal muscle has been suggested to release anti-inflammatory factors, but the effect of myotube-derived EVs on macrophages is unknown. As an anti-inflammatory mechanism of macrophages, the immune responsive gene 1 (IRG1)-itaconate pathway is essential. In this study, we show that skeletal muscle-derived EVs suppress macrophage inflammatory responses, upregulating the IRG1-itaconate pathway. C2C12 myoblasts were differentiated into myotubes and EVs were extracted by ultracentrifugation. Skeletal myotube-derived EVs were administered to mouse bone marrow-derived macrophages, then lipopolysaccharide (LPS) stimulation was performed and inflammatory cytokine expression was measured by RT-qPCR. Metabolite abundance in macrophages after addition of EVs was measured by CE/MS, and IRG1 expression was measured by RT-PCR. Furthermore, RNA-seq analysis was performed on macrophages after EV treatment. EVs attenuated the expression of LPS-induced pro-inflammatory factors in macrophages. Itaconate abundance and IRG1 expression were significantly increased in the EV-treated group. RNA-seq analysis revealed activation of the PI3K-Akt and JAK-STAT pathways in macrophages after EV treatment. The most abundant miRNA in myotube EVs was miR-206-3p, followed by miR-378a-3p, miR-30d-5p, and miR-21a-5p. Skeletal myotube EVs are supposed to increase the production of itaconate via upregulation of IRG1 expression and exhibited an anti-inflammatory effect in macrophages. This anti-inflammatory effect was suggested to involve the PI3K-Akt and JAK-STAT pathways. The miRNA profiles within EVs implied that miR-206-3p, miR-378a-3p, miR-30d-5p, and miR-21a-5p may be responsible for the anti-inflammatory effects of the EVs. In summary, in this study we showed that myotube-derived EVs prevent macrophage inflammatory responses by activating the IRG1-itaconate pathway.
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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：
10.1073/pnas.1521230113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Kowal, Joanna;Arras, Guillaume;Thery, Clotilde
通讯作者：
Thery, Clotilde
细胞外囊泡：分子组成和吸附到多种微生物上。
影响因子：
5.1
作者：
Biller, Steven J.;Lundeen, Rachel A.;Hmelo, Laura R.;Becker, Kevin W.;Arellano, Aldo A.;Dooley, Keven;Heal, Katherine R.;Carlson, Laura T.;Van Mooy, Benjamin A. S.;Ingalls, Anitra E.;Chisholm, Sallie W.
通讯作者：
Chisholm, Sallie W.
Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
24.8
作者：
Ogger, Patricia P.;Albers, Gesa J.;Byrne, Adam J.
通讯作者：
Byrne, Adam J.