Interleukin-6 (IL-6) signaling is a crucial regulatory event important for many biological functions, such as inflammation and tissue regeneration. Accordingly, several pathological conditions are associated with dysregulated IL-6 activity, making it an attractive therapeutic target. For instance, blockade of IL-6 or its α-receptor (IL-6R) by monoclonal antibodies has been successfully used to treat rheumatoid arthritis. However, based on different signaling modes, IL-6 function varies between pro- and anti-inflammatory activity, which is critical for therapeutic intervention. So far, three modes of IL-6 signaling have been described, the classic anti-inflammatory signaling, as well as pro-inflammatory trans-signaling, and trans-presentation. The IL-6/IL-6R complex requires an additional β-receptor (gp130), which is expressed on almost all cells of the human body, to induce STAT3 (signal transducer and activator of signal transcription 3) phosphorylation and subsequent transcriptional regulation. In contrast, the IL-6R is expressed on a limited number of cells, including hepatocytes and immune cells. However, the proteolytic release of the IL-6R enables trans-signaling on cells expressing gp130 only. Here, we demonstrate a fourth possibility of IL-6 signaling that we termed joint reconstituted signaling (JRS). We show that IL-6R on extracellular vesicles (EVs) can also be transported to and fused with other cells that lack the IL-6R on their surface. Importantly, JRS via EVs induces delayed STAT3 phosphorylation compared to the well-established trans-signaling mode. EVs isolated from human serum were already shown to carry the IL-6R, and thus this new signaling mode should be considered with regard to signal intervention.

中文翻译：

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IL-6受体通过细胞外囊泡的联合重建信号。

白介素6（IL-6）信号传导是至关重要的调节事件，对许多生物学功能（例如炎症和组织再生）很重要。因此，几种病理状况与IL-6活性失调有关，使其成为有吸引力的治疗靶标。例如，单克隆抗体阻断IL-6或其α受体（IL-6R）已成功用于治疗类风湿关节炎。然而，基于不同的信号传导模式，IL-6功能在促炎和抗炎活性之间有所不同，这对于治疗干预至关重要。到目前为止，已经描述了IL-6信号传导的三种模式，即经典的抗炎信号传导，促炎性反信号传导和反信号呈递。IL-6 / IL-6R复合物需要额外的β受体（gp130），它在人体几乎所有细胞上表达，以诱导STAT3（信号转导和信号转录激活剂3）的磷酸化和随后的转录调控。相反，IL-6R在有限数量的细胞中表达，包括肝细胞和免疫细胞。但是，IL-6R的蛋白水解释放仅能在表达gp130的细胞上进行反信号转导。在这里，我们证明了我们称之为IL-6信号传导的第四种可能性联合重建信令（JRS）。我们显示，细胞外囊泡（EVs）上的IL-6R也可以转运至与其他在其表面缺少IL-6R的细胞融合。重要的是，与公认的跨信号模式相比，通过电动汽车进行的JRS诱导了STAT3磷酸化的延迟。从人血清中分离出的电动汽车已经显示出携带IL-6R，因此在信号干预方面应考虑这种新的信号传导模式。