Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.
Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.
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DOI：
10.1096/fj.201600856r
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Keswani SG
中科院分区：
文献类型：
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作者：
Balaji S;Wang X;King A;Le LD;Bhattacharya SS;Moles CM;Butte MJ;de Jesus Perez VA;Liechty KW;Wight TN;Crombleholme TM;Bollyky PL;Keswani SG
细胞因子IL-10在成人纤维化模型中具有有效的抗纤维化作用，但作用机制尚不清楚。在这里，我们报告了一个新的发现，IL-10触发信号转导和转录激活因子3（STAT 3）依赖性信号传导途径，调节透明质酸（HA）代谢，并驱动成人成纤维细胞合成富含HA的细胞周基质，模拟胎儿再生伤口愈合表型，减少纤维化。通过使用cre-lox介导的新的，可诱导的，成纤维细胞，角质形成细胞，和伤口特异性STAT 3敲低出生后小鼠加同基因成纤维细胞移植模型，我们证明了IL-10在出生后伤口的再生作用依赖于HA合成和成纤维细胞特异性STAT 3依赖性信号传导。IL-10诱导的HA合成对于再生性伤口愈合的重要性通过施用4-甲基伞形酮在鼠伤口模型中抑制HA合成来证明。尽管IL-10和STAT 3信号传导是完整的，但在该模型中由IL-10过表达诱导的抗纤维化修复表型被废除。我们的数据显示，IL-10的新作用超出了其公认的免疫调节机制。IL-10调节再生的、富含HA的伤口细胞外基质的成纤维细胞特异性形成的机会可能导致开发创新疗法，以减轻器官系统或疾病中的出生后纤维化，其中失调的炎症和HA相交。Balaji，S.，王，X.，King，A.，勒湖D、巴塔查里亚河美国，莫莱斯角M.，Butte，M. J.，德赫苏斯·佩雷斯，弗吉尼亚州，克雷蒂W.，怀特，T。N.，Crombleholme，T. M.的情况，波利基，P.L.，Keswani，S. G.白细胞介素-10介导的再生性出生后组织修复依赖于通过成纤维细胞特异性STAT 3信号传导调节透明质酸代谢。
The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)–dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox–mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3-knockdown postnatal mice—plus syngeneic fibroblast cell-transplant models—we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10–induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.—Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10–mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.