Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

Wenxia Wang; Swarna Bale; Jun Wei; Bharath Yalavarthi; Dibyendu Bhattacharyya; Jing Jing Yan; Hiam Abdala-Valencia; Dan Xu; Hanshi Sun; Roberta Goncalves Marangoni; Erica Herzog; Sergejs Berdnikovs; Stephen D Miller; Amr H. Sawalha; Pei Suen Tsou; Kentaro Awaji; Takashi Yamashita; Shinichi Sato; Yoshihide Asano; Chinnaswamy Tiruppathi; Anjana Yeldandi; Bettina C. Schock; Swati Bhattacharyya; John Varga

doi:10.1038/s41467-022-33767-y

Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

Wenxia Wang, Swarna Bale, Jun Wei, Bharath Yalavarthi, Dibyendu Bhattacharyya, Jing Jing Yan, Hiam Abdala-Valencia, Dan Xu, Hanshi Sun, Roberta Goncalves Marangoni, Erica Herzog, Sergejs Berdnikovs, Stephen D Miller, Amr H. Sawalha, Pei Suen Tsou, Kentaro Awaji, Takashi Yamashita, Shinichi Sato, Yoshihide Asano, Chinnaswamy TiruppathiAnjana Yeldandi, Bettina C. Schock, Swati Bhattacharyya^*, John Varga

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.

Original language	English (US)
Article number	6358
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33767-y
State	Published - Dec 2022

Funding

We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation. We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Cite this

Wang, W., Bale, S., Wei, J., Yalavarthi, B., Bhattacharyya, D., Yan, J. J., Abdala-Valencia, H., Xu, D., Sun, H., Goncalves Marangoni, R., Herzog, E., Berdnikovs, S., Miller, S. D., Sawalha, A. H., Tsou, P. S., Awaji, K., Yamashita, T., Sato, S., Asano, Y., ... Varga, J. (2022). Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs. Nature communications, 13(1), Article 6358. https://doi.org/10.1038/s41467-022-33767-y

@article{457c90a22384449e9716aec777fd205d,

title = "Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs",

abstract = "In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.",

author = "Wenxia Wang and Swarna Bale and Jun Wei and Bharath Yalavarthi and Dibyendu Bhattacharyya and Yan, {Jing Jing} and Hiam Abdala-Valencia and Dan Xu and Hanshi Sun and {Goncalves Marangoni}, Roberta and Erica Herzog and Sergejs Berdnikovs and Miller, {Stephen D} and Sawalha, {Amr H.} and Tsou, {Pei Suen} and Kentaro Awaji and Takashi Yamashita and Shinichi Sato and Yoshihide Asano and Chinnaswamy Tiruppathi and Anjana Yeldandi and Schock, {Bettina C.} and Swati Bhattacharyya and John Varga",

note = "Funding Information: We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation. Funding Information: We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-33767-y",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Wang, W, Bale, S, Wei, J, Yalavarthi, B, Bhattacharyya, D, Yan, JJ, Abdala-Valencia, H, Xu, D, Sun, H, Goncalves Marangoni, R, Herzog, E, Berdnikovs, S , Miller, SD, Sawalha, AH, Tsou, PS, Awaji, K, Yamashita, T, Sato, S, Asano, Y, Tiruppathi, C, Yeldandi, A, Schock, BC, Bhattacharyya, S & Varga, J 2022, 'Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs', Nature communications, vol. 13, no. 1, 6358. https://doi.org/10.1038/s41467-022-33767-y

TY - JOUR

T1 - Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

AU - Wang, Wenxia

AU - Bale, Swarna

AU - Wei, Jun

AU - Yalavarthi, Bharath

AU - Bhattacharyya, Dibyendu

AU - Yan, Jing Jing

AU - Abdala-Valencia, Hiam

AU - Xu, Dan

AU - Sun, Hanshi

AU - Goncalves Marangoni, Roberta

AU - Herzog, Erica

AU - Berdnikovs, Sergejs

AU - Miller, Stephen D

AU - Sawalha, Amr H.

AU - Tsou, Pei Suen

AU - Awaji, Kentaro

AU - Yamashita, Takashi

AU - Sato, Shinichi

AU - Asano, Yoshihide

AU - Tiruppathi, Chinnaswamy

AU - Yeldandi, Anjana

AU - Schock, Bettina C.

AU - Bhattacharyya, Swati

AU - Varga, John

N1 - Funding Information: We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation. Funding Information: We are grateful to members of the Scleroderma Research Laboratory, the staff of the Mouse Histology & Phenotyping Laboratory (MHPL), and the Northwestern University Skin Diseases Research and Imaging Cores for excellent technical support. We acknowledge the unreserved support from Dr Carol Feghali-Bostwick for providing lung biopsy specimens collected from SSc-ILD transplant biopsies and Jose Naranjo for providing an antisense-DREAM plasmid. The study was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS AR42309), and the Scleroderma Foundation. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.

AB - In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.

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U2 - 10.1038/s41467-022-33767-y

DO - 10.1038/s41467-022-33767-y

M3 - Article

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SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6358

ER -

Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

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