PU.1 控制成纤维细胞极化和组织纤维化,Nature

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PU.1 控制成纤维细胞极化和组织纤维化
Nature ( IF 50.5 ) Pub Date : 2019-01-30 , DOI: 10.1038/s41586-019-0896-x
Thomas Wohlfahrt ₁ , Simon Rauber ₁ , Steffen Uebe ₂ , Markus Luber ₁ , Alina Soare ₁ , Arif Ekici ₂ , Stefanie Weber ₁ , Alexandru-Emil Matei ₁ , Chih-Wei Chen ₁ , Christiane Maier ₁ , Emmanuel Karouzakis ₃ , Hans P Kiener ₄ , Elena Pachera ₃ , Clara Dees ₁ , Christian Beyer ₁ , Christoph Daniel ₅ , Kolja Gelse ₆ , Andreas E Kremer ₇ , Elisabeth Naschberger ₈ , Michael Stürzl ₈ , Falk Butter ₉ , Michael Sticherling ₁₀ , Susetta Finotto ₁₁ , Alexander Kreuter ₁₂ , Mark H Kaplan ₁₃ , Astrid Jüngel ₃ , Steffen Gay ₃ , Stephen L Nutt _{14,

15} , David W Boykin ₁₆ , Gregory M K Poon ₁₆ , Oliver Distler ₃ , Georg Schett ₁ , Jörg H W Distler ₁ , Andreas Ramming ₁

Affiliation

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Institute of Human Genetics, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Department of Nephropathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Department of Trauma Surgery, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Internal Medicine 1, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Quantitative Proteomics Group, Institute of Molecular Biology, Mainz, Germany.
Department of Dermatology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, Germany.
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
The Walter and Eliza Hall Institute of Medical Research, Molecular Immunology Division, Parkville, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Department of Chemistry, Georgia State University, Atlanta, GA, USA.

成纤维细胞是多态性细胞，在器官形态发生、组织稳态和免疫反应中具有多效性。在纤维化疾病中，成纤维细胞合成大量细胞外基质，从而导致瘢痕形成和器官衰竭。相比之下，关节炎中成纤维细胞的一个标志性特征是细胞外基质的降解，这是因为金属蛋白酶和降解酶的释放以及随后的组织破坏。驱动这些功能相反的成纤维细胞促纤维化和促炎表型的机制仍然未知。在这里，我们将转录因子 PU.1 确定为促纤维化基因表达程序的重要调节因子。通常控制 PU 表达的转录和转录后机制之间的相互作用。1 表达在各种纤维化疾病中受到干扰，导致 PU.1 的上调，纤维化相关基因组的诱导和产生细胞外基质的促纤维化成纤维细胞的表型转换。相比之下，PU.1 的药理学和基因失活会破坏纤维化网络，并使纤维化成纤维细胞重新编程为静息成纤维细胞，从而导致多个器官中纤维化的消退。转录因子 PU.1 是促纤维化基因的重要调节因子成纤维细胞中的表达程序；PU.1 表达在各种纤维化疾病中上调，而 PU.1 的失活会诱导许多器官中纤维化的消退。纤维化相关基因组的诱导和细胞外基质产生的促纤维化成纤维细胞的表型转换。相比之下，PU.1 的药理学和基因失活会破坏纤维化网络，并使纤维化成纤维细胞重新编程为静息成纤维细胞，从而导致多个器官中纤维化的消退。转录因子 PU.1 是促纤维化基因的重要调节因子成纤维细胞中的表达程序；PU.1 表达在各种纤维化疾病中上调，而 PU.1 的失活会诱导许多器官中纤维化的消退。纤维化相关基因组的诱导和细胞外基质产生的促纤维化成纤维细胞的表型转换。相比之下，PU.1 的药理学和基因失活会破坏纤维化网络，并使纤维化成纤维细胞重新编程为静息成纤维细胞，从而导致多个器官中纤维化的消退。转录因子 PU.1 是促纤维化基因的重要调节因子成纤维细胞中的表达程序；PU.1 表达在各种纤维化疾病中上调，而 PU.1 的失活会诱导许多器官中纤维化的消退。转录因子 PU.1 是成纤维细胞中促纤维化基因表达程序的重要调节因子；PU.1 表达在各种纤维化疾病中上调，而 PU.1 的失活会诱导许多器官中纤维化的消退。转录因子 PU.1 是成纤维细胞中促纤维化基因表达程序的重要调节因子；PU.1 表达在各种纤维化疾病中上调，而 PU.1 的失活会诱导许多器官中纤维化的消退。

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PU.1 controls fibroblast polarization and tissue fibrosis

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.The transcription factor PU.1 is an essential regulator of the pro-fibrotic gene expression program in fibroblasts; PU.1 expression is upregulated in various fibrotic diseases, whereas inactivation of PU.1 induces regression of fibrosis in a number of organs.

更新日期：2019-01-30

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