Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13
Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13
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DOI：
10.1073/pnas.0700021104
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发表时间：
2007-02-20
影响因子：
11.1
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Aliprantis, Antonios O.;Wang, Jingsong;Glimcher, Laurie H.
组织重构伴纤维化是许多人类疾病的主要病理生理机制。系统性硬化症是一种罕见的，通常是致命的，病因不明的疾病，表现为皮肤纤维化（硬皮病）和内脏过多的结缔组织沉积。目前，没有可用的抗纤维化治疗方法，这反映了我们对这一过程缺乏了解。硬皮病的动物模型是解剖控制纤维化的转录因子和细胞因子的有用工具。2型细胞因子（如tgf - β和IL-4）比1型细胞因子（如ifn - γ）的不成比例的增加被认为是硬皮病发病的基础。在这项研究中，我们发现缺乏T细胞（T-bet）中表达的转录因子T-box （T-bet是1型免疫的主要调节因子）的小鼠对博莱霉素诱导的皮肤硬化表现出更高的敏感性。尽管T-bet在适应性免疫中的作用已经得到了证实，但我们还发现，缺乏T细胞和B细胞的RAG2（-/-）小鼠对博来霉素诱导的硬皮病易感，RAG2/T-bet双缺陷小鼠对博来霉素的敏感性与T-bet（-/-）小鼠相比有所增加。此外，在该模型中，T细胞中T-bet的过表达并不影响皮肤硬化的诱导。最后，我们发现IL-13是该模型中受T-bet调控的促纤维化细胞因子。总之，我们得出结论，T-bet通过先天免疫细胞中il -13依赖性途径作为皮肤硬化的抑制因子。T-bet及其转录网络代表了治疗系统性硬化症和其他纤维化疾病的一个有吸引力的靶点。
Tissue remodeling with fibrosis is a predominant pathophysiological mechanism of many human diseases. Systemic sclerosis is a rare, often lethal, disorder of unknown etiology manifested by dermal fibrosis (scleroderma) and excessive connective tissue deposition in internal organs. Currently, there are no available antifibrotic therapeutics, a reflection of our lack of understanding of this process. Animal models of scleroderma are useful tools to dissect the transcription factors and cytokines that govern fibrosis. A disproportionate increase of type 2 cytokines, like TGF-beta and IL-4, more than type 1 cytokines, like IFN-gamma, is thought to underlie the pathogenesis of scleroderma. In this study, we show that mice deficient in the transcription factor T-box expressed in T cells (T-bet), a master regulator of type 1 immunity, display increased sensitivity to bleomycin-induced dermal sclerosis. Despite the well-established role of T-bet in adaptive immunity, we also show that RAG2(-/-) mice, which lack T and B cells, are vulnerable to bleomycin-induced scleroderma and that RAG2/T-bet double-deficient mice maintain the increased sensitivity to bleomycin observed in T-bet(-/-.) mice. Furthermore, overexpression of T-bet in T cells does not affect the induction of skin sclerosis in this model. Lastly, we show that IL-13 is the profibrotic cytokine regulated by T-bet in this model. Together, we conclude that T-bet serves as a repressor of dermal sclerosis through an IL-13-dependent pathway in innate immune cells. T-bet, and its transcriptional network, represent an attractive target for the treatment of systemic sclerosis and other fibrosing disorders.