Extracellular vesicles (EVs) have emerged as key regulators of immune function across multiple diseases. Severe burn injury is a devastating trauma with significant immune dysfunction that results in an ∼12% mortality rate due to sepsis-induced organ failure, pneumonia, and other infections. Severe burn causes a biphasic immune response: an early (0–72 h) hyper-inflammatory state, with release of damage-associated molecular pattern molecules, such as high-mobility group protein 1 (HMGB1), and proinflammatory cytokines (e.g., IL-1β), followed by an immunosuppressive state (1–2+ wk post injury), associated with increased susceptibility to life-threatening infections. We have reported that early after severe burn injury HMGB1 and IL-1β are enriched in plasma EVs. Here we tested the impact of EVs isolated after burn injury on phenotypic and functional consequences in vivo and in vitro using adoptive transfers of EV. EVs isolated early from mice that underwent a 20% total body surface area burn injury (burn EVs) caused similar hallmark cytokine responses in naïve mice to those seen in burned mice. Burn EVs transferred to RAW264.7 macrophages caused similar functional (i.e., cytokine secretion) and immune gene expression changes seen with their associated phase of post-burn immune dysfunction. Burn EVs isolated early (24 h) induced MCP-1, IL-12p70, and IFNγ, whereas EVs isolated later blunted RAW proinflammatory responses to bacterial endotoxin (LPS). We also describe significantly increased HMGB1 cargo in burn EVs purified days 1 to 7 after injury. Thus, burn EVs cause immune outcomes in naïve mice and macrophages similar to findings after severe burn injury, suggesting EVs promote post-burn immune dysfunction.

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严重烧伤后释放的血浆细胞外囊泡调节巨噬细胞表型和功能

细胞外囊泡 (EV) 已成为多种疾病免疫功能的关键调节剂。严重烧伤是一种具有严重免疫功能障碍的毁灭性创伤，由于败血症引起的器官衰竭、肺炎和其他感染导致约 12% 的死亡率。重度烧伤引起双相免疫反应：早期（0-72 小时）高炎症状态，伴随损伤相关分子模式分子的释放，如高迁移率基团蛋白 1 (HMGB1) 和促炎细胞因子（如 IL -1β），然后是免疫抑制状态（受伤后 1-2+ 周），这与对危及生命的感染的易感性增加有关。我们已经报道，在严重烧伤后早期，HMGB1 和 IL-1β 富含血浆 EV。在这里，我们使用 EV 的过继转移测试了烧伤后分离的 EV 对体内和体外表型和功能后果的影响。早期从经历 20% 全身表面积烧伤（烧伤 EV）的小鼠中分离出的 EV 在幼稚小鼠中引起与在烧伤小鼠中观察到的相似的标志性细胞因子反应。转移到 RAW264.7 巨噬细胞的烧伤 EV 引起类似的功能（即细胞因子分泌）和免疫基因表达变化，与烧伤后免疫功能障碍的相关阶段可见。早期（24 小时）分离的烧伤 EV 诱导 MCP-1、IL-12p70 和 IFNγ，而后来分离的 EV 减弱了对细菌内毒素 (LPS) 的 RAW 促炎反应。我们还描述了在受伤后 1 至 7 天纯化的烧伤 EV 中 HMGB1 货物的显着增加。因此，