Exosomes Derived From Septic Mouse Serum Modulate Immune Responses via Exosome-Associated Cytokines
Exosomes Derived From Septic Mouse Serum Modulate Immune Responses via Exosome-Associated Cytokines
复制标题
源自脓毒症小鼠血清的外泌体通过外泌体相关细胞因子调节免疫反应
DOI：
10.3389/fimmu.2019.01560
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发表时间：
2019-07-12
影响因子：
7.3
通讯作者：
Jiang, Yong
中科院分区：
文献类型：
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作者：
Gao, Kun;Jin, Jingmiao;Jiang, Yong
脓毒症是一种危及生命的病症，由感染引发的免疫反应所致，血液中细胞因子/趋化因子水平的大幅升高在脓毒症的进展中起着关键作用。血清外泌体是具有多种生物学功能的纳米囊泡，在抗原呈递、细胞间信号通讯、炎症反应和免疫监视中发挥作用。然而，其生物学功能及相关分子基础仍有待阐明。在本研究中，我们探究了脓毒症小鼠外泌体中携带的细胞因子/趋化因子谱，并探索了用脓毒症小鼠来源的外泌体处理T细胞时的免疫调节机制。血液中的细胞因子/趋化因子以可溶形式和不可溶的外泌体形式存在；在脂多糖（LPS）攻击的小鼠血液中，这两种形式的细胞因子/趋化因子谱呈现出不同的动态变化。脓毒症小鼠的外泌体诱导Th1/Th2细胞分化，而针对白细胞介素 - 12（IL - 12）和白细胞介素 - 4（IL - 4）的特异性抗体可阻断这一过程。此外，这些外泌体显著增强了T淋巴细胞的增殖和迁移。再者，通过静脉注射预先给予外泌体可抑制炎症反应，减轻肺和肝组织损伤，并延长盲肠结扎穿孔（CLP）小鼠的存活时间。我们的研究结果表明，富含细胞因子/趋化因子的外泌体在脓毒症过程中对T细胞分化、增殖和趋化起着关键作用，对盲肠结扎穿孔（CLP）小鼠具有保护作用。因此，这些发现不仅加深了我们对外泌体在脓毒症中作用的理解，还为治疗应用提供了潜在靶点。
Sepsis is a life-threatening condition caused by an immune response triggered by infection, and highly elevated cytokine/chemokine levels in the blood play crucial roles in the progression of sepsis. Serum exosomes are nanovesicles that have multiple biological functions, playing roles in antigen presentation, intercellular signal communication, inflammatory response and immune surveillance. However, the biological functions and related molecular bases remain to be elucidated. In this study, we investigated the profiles of cytokines/chemokines harbored in the exosomes of septic mice and explored the mechanisms of immunomodulation on T cells treated with exosomes harvested from septic mice. Blood cytokines/chemokines existed in both the soluble form and in the insoluble exosomal form; the profiles of the cytokines/chemokines in these two forms displayed different dynamics in the blood of mice challenged with LPS. Exosomes from septic mice induced the differentiation of Th1/Th2 cells, which was blocked by specific antibodies targeting IL-12 and IL-4. In addition, these exosomes significantly augmented the proliferation and migration of T lymphocytes. Furthermore, preadministration of exosomes by intravenous injection restrained the inflammatory response, attenuated lung and liver tissue damage, and prolonged the survival of cecal ligation and puncture (CLP) mice. Our results indicate that exosomes enriched with cytokines/chemokines play critical roles in T cell differentiation, proliferation and chemotaxis during the sepsis process and have a protective effect on cecal ligation and puncture (CLP) mice. Thus, these findings not only strengthen our understanding of the role of sepsis via exosomes but also provide potential targets for therapeutic applications.