Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype.
Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype.
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DOI：
10.1038/s41598-020-80509-5
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发表时间：
2021-01-08
影响因子：
4.6
通讯作者：
Haraldsen G
中科院分区：
文献类型：
--
作者：
Gatti F;Mia S;Hammarström C;Frerker N;Fosby B;Wang J;Pietka W;Sundnes O;Hol J;Kasprzycka M;Haraldsen G
白细胞介素（IL）-33是一种细胞因子，其似乎通过经由其受体ST 2（IL-33 R/IL 1 RL 1）的信号传导来介导纤维化。然而，它也是一种蛋白质，在合成后被分选到细胞核，在那里它似乎影响染色质折叠。在这里，我们描述了一个新的作用，细胞核IL-33在调节成纤维细胞表型在小鼠肾纤维化驱动的单侧输尿管梗阻。IL-33缺乏的肾脏结扎后24小时的转录谱显示纤维化基因的表达增强和参与细胞外基质形成和重塑的基因集的富集。这些变化依赖于IL-33的细胞内效应，因为用IL-33中和抗体（可阻止IL-33 R/ST 2L受体信号传导）处理时，这些变化不会重现，在IL-33 R/ST 2缺陷型肾脏中也未观察到这些变化。为了进一步探索IL-33的细胞内功能，我们建立了人成纤维细胞的转录谱，观察到IL-33的敲低使转录谱从炎性表型向肌成纤维细胞表型倾斜，反映在更高水平的C 0 L3 A1、C 0 L5 A1和transgelin蛋白，以及更低水平的IL 6、CXCL 8、CLL 7和CCL 8的表达。总之，我们的研究结果表明，成纤维细胞中的细胞核IL-33抑制了最初的促纤维化反应，直到持续的刺激，如UUO所执行的，可以覆盖这种保护机制。
Interleukin (IL)-33 is a cytokine that appears to mediate fibrosis by signaling via its receptor ST2 (IL-33R/IL1RL1). It is also, however, a protein that after synthesis is sorted to the cell nucleus, where it appears to affect chromatin folding. Here we describe a novel role for nuclear IL-33 in regulating the fibroblast phenotype in murine kidney fibrosis driven by unilateral ureteral obstruction. Transcriptional profiling of IL-33-deficient kidneys 24 h after ligation revealed enhanced expression of fibrogenic genes and enrichment of gene sets involved in extracellular matrix formation and remodeling. These changes relied on intracellular effects of IL-33, because they were not reproduced by treatment with a neutralizing antibody to IL-33 that prevents IL-33R/ST2L receptor signaling nor were they observed in IL-33R/ST2-deficient kidneys. To further explore the intracellular function of IL-33, we established transcription profiles of human fibroblasts, observing that knockdown of IL-33 skewed the transcription profile from an inflammatory towards a myofibroblast phenotype, reflected in higher levels of COL3A1, COL5A1 and transgelin protein, as well as lower expression levels of IL6, CXCL8, CLL7 and CCL8. In conclusion, our findings suggest that nuclear IL-33 in fibroblasts dampens the initial profibrotic response until persistent stimuli, as enforced by UUO, can override this protective mechanism.
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DOI：
10.1073/pnas.0812690106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Cayrol, Corinne;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
DOI：
10.1016/j.bbrc.2014.06.111
发表时间：
2014-08-15
影响因子：
3.1
作者：
Shao, Dongmin;Perros, Frederic;Wort, Stephen J.
通讯作者：
Wort, Stephen J.
影响因子：
32.4
作者：
McHedlidze T;Waldner M;Zopf S;Walker J;Rankin AL;Schuchmann M;Voehringer D;McKenzie AN;Neurath MF;Pflanz S;Wirtz S
通讯作者：
Wirtz S
影响因子：
7.7
作者：
Roussel, Lucie;Erard, Monique;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe