Transient inflammatory response mediated by interleukin-1β is required for proper regeneration in zebrafish fin fold.
Transient inflammatory response mediated by interleukin-1β is required for proper regeneration in zebrafish fin fold.
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DOI：
10.7554/elife.22716
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发表时间：
2017-02-23
期刊：
影响因子：
7.7
通讯作者：
Kawakami A
中科院分区：
文献类型：
--
作者：
Hasegawa T;Hall CJ;Crosier PS;Abe G;Kawakami K;Kudo A;Kawakami A
细胞对损伤的反应对于完整的组织再生至关重要，但其潜在的过程仍然没有完全阐明。我们以前曾报道，骨髓缺陷型斑马鱼突变体显示再生细胞凋亡鳍折叠再生过程中。在这里，我们发现细胞凋亡表型是由白细胞介素1 β（il 1b）的长期表达诱导的。髓样细胞被认为是IL 1B的主要来源，但我们表明，上皮细胞表达IL 1B在组织损伤的反应，并启动炎症反应，其决议由巨噬细胞是必要的再生细胞的生存。我们进一步表明，Il 1b通过调节再生诱导基因的表达在正常鳍褶再生中起着至关重要的作用。我们的研究表明，由巨噬细胞调节的适当水平的Il 1b信号传导和组织炎症在组织再生中起着至关重要的作用。http://dx.doi.org/10.7554/eLife.22716.001动物和其他多细胞生物都至少有一些再生失去或受伤组织的能力。斑马鱼在这方面特别擅长，因为它们可以用原件的精确复制品替换损坏或丢失的身体部位。2015年，一组研究人员发现，一些缺乏血细胞（包括免疫细胞）的突变斑马鱼无法再生失去的组织。这是因为准备再生的细胞反而死亡，但尚不清楚为什么会发生这种情况。许多免疫细胞在抵抗感染和应对组织损伤方面发挥作用。当组织受损时，该区域通常会发炎，因为称为巨噬细胞的白色血细胞聚集到受损区域以保护其免受感染并清除受损细胞。Hasegawa等人-包括参与2015年研究的几名研究人员-使用遗传方法来研究炎症在斑马鱼组织再生中的作用。实验表明，与正常斑马鱼相比，突变鱼中与炎症有关的几种基因-包括一种称为白细胞介素1b的基因-在更长的时间内处于活跃状态。该基因产生一种信号蛋白，这种长时间的活性导致引发的再生细胞死亡。然而，如果白细胞介素1b活性被巨噬细胞迅速抑制，细胞可以存活。实验还表明，为了使组织正常再生，白细胞介素1b只需要在短时间内保持活性。研究结果表明，组织再生需要一些炎症，但更严重的炎症反应可能会阻止这一过程。未来的挑战将是确定巨噬细胞产生的信号，以抑制炎症，使组织再生。这些抗炎信号可能有潜力用作治疗慢性炎症疾病和促进人类组织再生潜力的药物。DOI：http://dx.doi.org/10.7554/eLife.22716.002网站
Cellular responses to injury are crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by prolonged expression of interleukin 1 beta (il1b). Myeloid cells are considered to be the principal source of Il1b, but we show that epithelial cells express il1b in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for survival of regenerative cells. We further show that Il1b plays an essential role in normal fin fold regeneration by regulating expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned by macrophages, play a crucial role in tissue regeneration. DOI: http://dx.doi.org/10.7554/eLife.22716.001 Animals and other multicellular organisms all have at least some ability to regenerate lost or wounded tissues. Zebrafish are particularly good at this to the extent that they can replace damaged or lost body parts with exact replicas of the originals. In 2015, a team of researchers found that some mutant zebrafish that lack blood cells including immune cells are unable to regenerate lost tissues. This is because the cells that are primed to regenerate die instead, but it was not clear why this happens. Many immune cells have roles in fighting infection and in responding to tissue damage.When a tissue is damaged, the area often becomes inflamed as white blood cells called macrophages flock to the damaged area to protect it from infection and remove damaged cells. Hasegawa et al. – who include several researchers involved in the 2015 study – used genetic approaches to investigate the role of inflammation in tissue regeneration in zebrafish. The experiments show that several genes involved in inflammation – including one called interleukin 1b – were active over longer periods of time in the mutant fish compared with normal zebrafish. The gene produces a signal protein and this prolonged activity causes the primed regenerative cells to die. However, the cells can survive if interleukin 1b activity is quickly suppressed by macrophages. The experiments also show that, in order for tissues to regenerate properly, interleukin 1b needs to be active for only a short period of time. The findings reveal that some inflammation is needed for tissues to regenerate, but that a more severe inflammatory response can block the process. A future challenge will be to identify the signals that macrophages produce to suppress inflammation to allow tissues to regenerate. These anti-inflammatory signals may have the potential to be used as drugs to cure chronic inflammatory diseases and boost tissue regeneration potential in humans. DOI: http://dx.doi.org/10.7554/eLife.22716.002