Section of Anaesthetics, Pain Medicine, and Intensive Care, Faculty of Medicine, Chelsea and Westminster Hospital, Imperial College London, London, United Kingdom.
Heart Science Centre, Harefield Hospital, National Heart and Lung Institute, Imperial College London, Harefield, United Kindom.
FASEB J. 2019 May;33(5):6442-6455. doi: 10.1096/fj.201802386R. Epub 2019 Feb 18.
Cellular stress or injury induces release of endogenous danger signals such as ATP, which plays a central role in activating immune cells. ATP is essential for the release of nonclassically secreted cytokines such as IL-1β but, paradoxically, has been reported to inhibit the release of classically secreted cytokines such as TNF. Here, we reveal that ATP does switch off soluble TNF (17 kDa) release from LPS-treated macrophages, but rather than inhibiting the entire TNF secretion, ATP packages membrane TNF (26 kDa) within microvesicles (MVs). Secretion of membrane TNF within MVs bypasses the conventional endoplasmic reticulum- and Golgi transport-dependent pathway and is mediated by acid sphingomyelinase. These membrane TNF-carrying MVs are biologically more potent than soluble TNF , producing significant lung inflammation in mice. Thus, ATP critically alters TNF trafficking and secretion from macrophages, inducing novel unconventional membrane TNF signaling MVs without direct cell-to-cell contact. These data have crucial implications for this key cytokine, particularly when therapeutically targeting TNF in acute inflammatory diseases.-Soni, S., O'Dea, K. P., Tan, Y. Y., Cho, K., Abe, E., Romano, R., Cui, J., Ma, D., Sarathchandra, P., Wilson, M. R., Takata, M. ATP redirects cytokine trafficking and promotes novel membrane TNF signaling microvesicles.
细胞应激或损伤会诱导内源性危险信号的释放，如 ATP，它在激活免疫细胞中起着核心作用。ATP 对于非经典分泌细胞因子（如 IL-1β）的释放是必不可少的，但矛盾的是，据报道，它会抑制经典分泌细胞因子（如 TNF）的释放。在这里，我们揭示了 ATP 确实会关闭 LPS 处理的巨噬细胞中可溶性 TNF（17 kDa）的释放，但 ATP 不是抑制整个 TNF 分泌，而是将膜 TNF（26 kDa）包装在微泡（MVs）中。MV 内的膜 TNF 分泌绕过了传统的内质网和高尔基体依赖的途径，由酸性鞘磷脂酶介导。这些携带膜 TNF 的 MV 比可溶性 TNF 具有更强的生物学活性，在小鼠中产生显著的肺部炎症。因此，ATP 从巨噬细胞中显著改变 TNF 的运输和分泌，诱导新型非经典膜 TNF 信号 MV，而无需直接细胞间接触。这些数据对这种关键细胞因子具有至关重要的意义，特别是在急性炎症性疾病中靶向治疗 TNF 时。
