Abstract：
BACKGROUND: Fibrosis results from excessive scar formation after tissue injury. Injured cells release alarmins such as interleukin 1 (IL-1) α and β as primary mediators initiating tissue repair. However, how alarmins from different cell types differentially regulate fibrosis remains to be explored.
METHODS: Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis. The two fibrotic animal model triggered by bleomycin and CCl4 were used to study the effects of endothelial paracrine/angiocrine IL-1α in fibrotic progression. Human umbilical vein endothelial cells (HUVEC) were performed to explore the production of angiocrine IL-1α at both transcriptional and post-transcriptional levels in vitro.
RESULTS: We found that endothelial paracrine/angiocrine IL-1α primarily promotes lung and liver fibrosis during the early phase of organ repair. By contrast, myeloid cell-specific ablation of IL-1α in mice resulted in little influence on fibrosis, suggesting the specific pro-fibrotic role of IL-1α from endothelial cell but not macrophage. In vitro study revealed a coordinated regulation of IL-1α production in human primary endothelial cells at both transcriptional and post-transcriptional levels. Specifically, the transcription of IL-1α is regulated by RIPK1, and after caspase-8 (CASP8) cleaves the precursor form of IL-1α, its secretion is triggered by ion channel Pannexin 1 upon CASP8 cleavage.
CONCLUSIONS: Endothelial cell-produced IL-1α plays a unique role in promoting organ fibrosis. Furthermore, the release of this angiocrine alarmin relies on a unique molecular mechanism involving RIPK1, CASP8, and ion channel Pannexin 1.
METHODS: Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis. The two fibrotic animal model triggered by bleomycin and CCl4 were used to study the effects of endothelial paracrine/angiocrine IL-1α in fibrotic progression. Human umbilical vein endothelial cells (HUVEC) were performed to explore the production of angiocrine IL-1α at both transcriptional and post-transcriptional levels in vitro.
RESULTS: We found that endothelial paracrine/angiocrine IL-1α primarily promotes lung and liver fibrosis during the early phase of organ repair. By contrast, myeloid cell-specific ablation of IL-1α in mice resulted in little influence on fibrosis, suggesting the specific pro-fibrotic role of IL-1α from endothelial cell but not macrophage. In vitro study revealed a coordinated regulation of IL-1α production in human primary endothelial cells at both transcriptional and post-transcriptional levels. Specifically, the transcription of IL-1α is regulated by RIPK1, and after caspase-8 (CASP8) cleaves the precursor form of IL-1α, its secretion is triggered by ion channel Pannexin 1 upon CASP8 cleavage.
CONCLUSIONS: Endothelial cell-produced IL-1α plays a unique role in promoting organ fibrosis. Furthermore, the release of this angiocrine alarmin relies on a unique molecular mechanism involving RIPK1, CASP8, and ion channel Pannexin 1.
摘要：
背景：纤维化是组织损伤后过度瘢痕形成的结果。损伤的细胞释放诸如白细胞介素1(IL-1)α和β的警报因子作为启动组织修复的主要介质。然而,来自不同细胞类型的警报如何差异调节纤维化仍有待探索。
方法：这里，我们使用组织特异性敲除策略来说明内皮细胞衍生的IL-1α对肺和肝纤维化的独特贡献。使用博来霉素和CCl4触发的两种纤维化动物模型来研究内皮旁分泌/血管分泌IL-1α在纤维化进展中的作用。进行人脐静脉内皮细胞（HUVEC）以探索体外转录和转录后水平的血管分泌IL-1α的产生。
结果：我们发现内皮旁分泌/血管分泌IL-1α在器官修复的早期阶段主要促进肺和肝纤维化。相比之下,小鼠骨髓细胞特异性消融IL-1α对纤维化的影响很小，提示来自内皮细胞而不是巨噬细胞的IL-1α的特异性促纤维化作用。体外研究揭示了人原代内皮细胞中IL-1α产生在转录和转录后水平上的协调调节。具体来说,IL-1α的转录受RIPK1的调控，在caspase-8（CASP8）裂解IL-1α的前体形式后，它的分泌是由离子通道Pannexin1在CASP8裂解时触发的。
结论：内皮细胞产生的IL-1α在促进器官纤维化中起着独特的作用。此外，这种血管分泌警报蛋白的释放依赖于涉及RIPK1,CASP8和离子通道Pannexin1的独特分子机制.
方法：这里，我们使用组织特异性敲除策略来说明内皮细胞衍生的IL-1α对肺和肝纤维化的独特贡献。使用博来霉素和CCl4触发的两种纤维化动物模型来研究内皮旁分泌/血管分泌IL-1α在纤维化进展中的作用。进行人脐静脉内皮细胞（HUVEC）以探索体外转录和转录后水平的血管分泌IL-1α的产生。
结果：我们发现内皮旁分泌/血管分泌IL-1α在器官修复的早期阶段主要促进肺和肝纤维化。相比之下,小鼠骨髓细胞特异性消融IL-1α对纤维化的影响很小，提示来自内皮细胞而不是巨噬细胞的IL-1α的特异性促纤维化作用。体外研究揭示了人原代内皮细胞中IL-1α产生在转录和转录后水平上的协调调节。具体来说,IL-1α的转录受RIPK1的调控，在caspase-8（CASP8）裂解IL-1α的前体形式后，它的分泌是由离子通道Pannexin1在CASP8裂解时触发的。
结论：内皮细胞产生的IL-1α在促进器官纤维化中起着独特的作用。此外，这种血管分泌警报蛋白的释放依赖于涉及RIPK1,CASP8和离子通道Pannexin1的独特分子机制.
