Involvement of extracellular vesicles in the progression, diagnosis, treatment, and prevention of whole-body ionizing radiation-induced immune dysfunction.
Involvement of extracellular vesicles in the progression, diagnosis, treatment, and prevention of whole-body ionizing radiation-induced immune dysfunction.
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细胞外囊泡参与全身电离辐射诱导的免疫功能障碍的进展、诊断、治疗和预防。
DOI：
10.3389/fimmu.2023.1188830
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
急性辐射综合征（ARS）是在暴露于高剂量电离辐射后发生的，其特征是免疫抑制和器官衰竭。目前，没有诊断方法来识别暴露的发生或严重程度，并且缓解ARS的治疗和预防策略有限。细胞外囊泡（EV）是细胞间通讯的介质，有助于许多疾病的免疫功能障碍。我们研究了EV货物是否可以识别全身照射（WBIR）暴露以及EV是否促进ARS免疫功能障碍。我们假设，来自间充质干细胞（MSC-EV）的有益EV将钝化ARS免疫功能障碍，并可能作为预防性辐射防护剂。小鼠接受WBIR（2或9戈伊），并在暴露后3天和7天评估EV。WBIR-EV的LC-MS/MS蛋白质组学分析发现了剂量相关的变化以及随剂量和时间点增加的候选蛋白质（共34个），如血栓烷-A合酶和淋巴细胞胞质蛋白2。仅在9戈伊后，超盆和Sarcalumenin增加，表明这些蛋白质可能表明高剂量/致死暴露。EV miRNA的分析鉴定了miR-376和miR-136，其通过两种剂量的WBIR分别增加高达200倍和60倍，并且选择的miRNA如miR-1839和miR-664仅在9戈伊时增加。WBIR-EV（9戈伊）在RAW 264.7巨噬细胞中具有生物活性并减弱对LPS的免疫应答，抑制与伤口愈合和吞噬体形成相关的经典信号传导途径。当暴露后3天给予MSC-EV时，MSC-EV轻微改变了小鼠脾脏中响应WBIR和联合辐射加烧伤暴露（RCI）的免疫基因表达变化。MSC-EV使某些关键免疫基因的表达正常化，如NFκBia和Cxcr 4（WBIR），Map 4k 1，Ccr 9和Cxcl 12（RCI），并降低了RCI后的血浆TNFα细胞因子水平。当以放射性方式（暴露前24小时和3小时）给药时，MSC-EV延长了9戈伊致死暴露的存活时间。因此，电动汽车是ARS的重要参与者。EV货物可用于诊断WBIR暴露，MSC-EV可作为辐射防护剂，以减弱有毒辐射暴露的影响。
Acute radiation syndrome (ARS) develops after exposure to high doses of ionizing radiation and features immune suppression and organ failure. Currently, there are no diagnostics to identify the occurrence or severity of exposure and there are limited treatments and preventative strategies to mitigate ARS. Extracellular vesicles (EVs) are mediators of intercellular communication that contribute to immune dysfunction across many diseases. We investigated if EV cargo can identify whole body irradiation (WBIR) exposure and if EVs promote ARS immune dysfunction. We hypothesized that beneficial EVs derived from mesenchymal stem cells (MSC-EVs) would blunt ARS immune dysfunction and might serve as prophylactic radioprotectants. Mice received WBIR (2 or 9 Gy) with assessment of EVs at 3 and 7 days after exposure. LC-MS/MS proteomic analysis of WBIR-EVs found dose-related changes as well as candidate proteins that were increased with both doses and timepoints (34 total) such as Thromboxane-A Synthase and lymphocyte cytosolic protein 2. Suprabasin and Sarcalumenin were increased only after 9 Gy suggesting these proteins may indicate high dose/lethal exposure. Analysis of EV miRNAs identified miR-376 and miR-136, which were increased up to 200- and 60-fold respectively by both doses of WBIR and select miRNAs such as miR-1839 and miR-664 were increased only with 9 Gy. WBIR-EVs (9 Gy) were biologically active and blunted immune responses to LPS in RAW264.7 macrophages, inhibiting canonical signaling pathways associated with wound healing and phagosome formation. When given 3 days after exposure, MSC-EVs slightly modified immune gene expression changes in the spleens of mice in response to WBIR and in a combined radiation plus burn injury exposure (RCI). MSC-EVs normalized the expression of certain key immune genes such as NFκBia and Cxcr4 (WBIR), Map4k1, Ccr9 and Cxcl12 (RCI) and lowered plasma TNFα cytokine levels after RCI. When given prophylactically (24 and 3 hours before exposure), MSC-EVs prolonged survival to the 9 Gy lethal exposure. Thus, EVs are important participants in ARS. EV cargo might be used to diagnose WBIR exposure, and MSC-EVs might serve as radioprotectants to blunt the impact of toxic radiation exposure.
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影响因子：
3.4
作者：
Kennedy AR;Maity A;Sanzari JK
通讯作者：
Sanzari JK
影响因子：
7.3
作者：
Keating R;McGargill MA
通讯作者：
McGargill MA
影响因子：
3.7
作者：
Jaafar L;Podolsky RH;Dynan WS
通讯作者：
Dynan WS
影响因子：
4.3
作者：
Desai, Chirag S.;Khan, Aisha;Maile, Robert
通讯作者：
Maile, Robert
影响因子：
2.2
作者：
Ardoin, Stacy P.;Pisetsky, David S.
通讯作者：
Pisetsky, David S.