ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1925

TGFβ Promotes Fibrosis By MYST1-Dependent Epigenetic Regulation of Autophagy

Ariella Zehender1, Neng-Yu Lin2, Adrian Stefanica3, Chih-Wei Chen4, Alina Soare5, Thomas Wohlfahrt6, Simon Rauber6, Christina Bergmann7, Andreas Ramming8, Oliver Distler9, Georg Schett10 and Jörg Distler5, 11Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 2Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 31Department of Internal Medicine 3 – Rheumatology and Immunology, University of Erlangen, Erlangen, Germany, 4Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, Erlangen, Germany, 5Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany, 6Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 7Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany, 8Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 9Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 10Department of Internal Medicine 3 – Rheumatology and Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg and University Hospital Erlangen, Erlangen, Germany

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: , , ,

Session Information

Date: Monday, November 6, 2017

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics I

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

Autophagy (Atg) is catabolic process allowing cells to degrade unnecessary or dysfunctional cellular organelles. Aberrant activation of Atg has been implicated into the pathogenesis of various diseases.

Methods:

We generated Atg7fl/flx Col1a2;CreER mice with selective inactivation of Atg in fibroblasts. The role of the Atg was investigated in the model of bleomycin- and TβRIact-induced dermal and pulmonary fibrosis. Overexpression of Myst1 and Beclin1 was achieved by adenoviral overexpression. ChIP and reporter assays were performed to study physical and functional interactions between MYST1 and SMAD3.

Results:

Atg is strongly activated in fibroblasts from SSc skin and also in experimental dermal and pulmonary fibrosis as compared to respective non-fibrotic control tissue with overexpression of ATG7 and of BECLIN, downregulation of the autophagy substrate p62 and activation of autophagy-dependent reporter activity. The aberrant activation of Atg has profound stimulatory effects on fibroblasts. Activation of Atg by forced expression of BECLIN1 promoted fibroblast-to-myofibroblast transition and stimulates the collagen release in vitro and in vivo. Moreover, inactivation of autophagy by fibroblast-specific knockout of Atg7prevented myofibroblast differentiation and ameliorated fibrosis, demonstrating that activation of Atg is both, sufficient and required, for fibroblast activation and tissue fibrosis. We also provide evidence that TGFβ activates Atg by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces Atg in fibrotic diseases by SMAD3-dependent downregulation of the H4K16-histoneacetlytransferase MYST1, which controls the expression of core components of the Atg machinery such as ATG7 and BECLIN1. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on Atg and re-establishes the epigenetic control of autophagy in fibrotic conditions. Overexpression of MYST1 prevents the aberrant activation of Atg, inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis.

Conclusion:

We demonstrate that the epigenetic control of Atg is disturbed by a TGFβ-dependent downregulation of MYST1 in SSc. The resulting uncontrolled activation of Atg promotes fibroblast-to-myofibroblast transition and tissue fibrosis. Restoration of the epigenetic control of autophagy limits the profibrotic effects of TGFβ and ameliorates experimental fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and altered epigenetics in fibrotic diseases.

Disclosure: A. Zehender, None; N. Y. Lin, None; A. Stefanica, None; C. W. Chen, None; A. Soare, None; T. Wohlfahrt, None; S. Rauber, None; C. Bergmann, None; A. Ramming, None; O. Distler, 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemomAb, EpiPharm, Ergonex, espeRare foundation, GSK,Roche-Genentech, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Seroda, 2; G. Schett, None; J. Distler, 4D Science, 1,Anamar Medical, Active Biotech, Array Biopma, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, Novartis, Sanofi-Aventis, UCB, 2,Actelion Pharmaceuticals US, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi, UCB, 5.

To cite this abstract in AMA style:

Zehender A, Lin NY, Stefanica A, Chen CW, Soare A, Wohlfahrt T, Rauber S, Bergmann C, Ramming A, Distler O, Schett G, Distler J. TGFβ Promotes Fibrosis By MYST1-Dependent Epigenetic Regulation of Autophagy [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/tgf%ce%b2-promotes-fibrosis-by-myst1-dependent-epigenetic-regulation-of-autophagy/. Accessed .

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