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PU.1 controls fibroblast polarization and tissue fibrosis

机译：PU.1控制成纤维细胞极化和组织纤维化

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摘要

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.
机译：成纤维细胞是在器官形态发生，组织稳态和免疫反应中具有多效性作用的多态细胞。在纤维化疾病中，成纤维细胞会合成大量的细胞外基质，从而引起瘢痕形成和器官衰竭。相比之下，成纤维细胞在关节炎中的标志性特征是由于金属蛋白酶和降解酶的释放以及随后的组织破坏而引起的细胞外基质的降解。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，我们确定转录因子PU.1是促纤维化基因表达程序的重要调控因子。正常控制PU.1表达的转录机制和转录后机制之间的相互作用在各种纤维化疾病中均受到干扰，从而导致PU.1上调，诱导与纤维化相关的基因集以及细胞外基质中的表型转换。产生促纤维化的成纤维细胞。相比之下，PU.1的药理和遗传失活会破坏纤维化网络，并使纤维化成纤维细胞重编程为静止的成纤维细胞，从而导致多个器官的纤维化消退。

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  • 来源
    《Nature》 |2019年第7744期|344-349|共6页
  • 作者

    Wohlfahrt Thomas; Rauber Simon; Uebe Steffen; Luber Markus; Soare Alina; Ekici Arif; Weber Stefanie; Matei Alexandru-Emil; Chen Chih-Wei; Maier Christiane; Karouzakis Emmanuel; Kiener Hans P.; Pachera Elena; Dees Clara; Beyer Christian; Daniel Christoph; Gelse Kolja; Kremer Andreas E.; Naschberger Elisabeth; Stuerzl Michael; Butter Falk; Sticherling Michael; Finotto Susetta; Kreuter Alexander; Kaplan Mark H.; Jungel Astrid; Gay Steffen; Nutt Stephen L.; Boykin David W.; Poon Gregory M. K.; Distler Oliver; Schett Georg; Distler Joerg H. W.; Ramming Andreas;

  • 作者单位

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Univ Hosp Zurich, Dept Rheumatol, Zurich, Switzerland;

    Med Univ Vienna, Dept Med 3, Div Rheumatol, Vienna, Austria;

    Univ Hosp Zurich, Dept Rheumatol, Zurich, Switzerland;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Nephropathol, Erlangen, Germany;

    Univ Klinikum Erlangen, Erlangen, Germany|Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Trauma Surg, Erlangen, Germany;

    Univ Klinikum Erlangen, Erlangen, Germany|Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med 1, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Surg, Div Mol & Expt Surg, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Surg, Div Mol & Expt Surg, Erlangen, Germany;

    Inst Mol Biol, Quantitat Prote Grp, Mainz, Germany;

    Univ Klinikum Erlangen, Erlangen, Germany|Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Dermatol, Erlangen, Germany;

    Univ Klinikum Erlangen, Erlangen, Germany|Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Mol Pneumol, Erlangen, Germany;

    Univ Witten Herdecke, HELIOS St Elisabeth Klin Oberhausen, Dept Dermatol Venereol & Allergol, Oberhausen, Germany;

    Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA;

    Univ Hosp Zurich, Dept Rheumatol, Zurich, Switzerland;

    Univ Hosp Zurich, Dept Rheumatol, Zurich, Switzerland;

    Walter & Eliza Hall Inst Med Res, Mol Immunol Div, Parkville, Vic, Australia|Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia;

    Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA;

    Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA;

    Univ Hosp Zurich, Dept Rheumatol, Zurich, Switzerland;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

    Friedrich Alexander Univ FAU Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany|Univ Klinikum Erlangen, Erlangen, Germany;

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