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 G 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 G 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

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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
Article number	6358
Number of pages	16
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-33767-y
Publication status	Published - 26 Oct 2022

Keywords

Mice, Knockout
Receptors, Adiponectin - metabolism
Animals
Disease Models, Animal
Cells, Cultured
Ubiquitins - metabolism
Bleomycin
Fibrosis
Skin - pathology
Scleroderma, Systemic - metabolism
Signal Transduction - genetics
Transforming Growth Factor beta - metabolism
Mice
Fibroblasts - metabolism

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Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
© 2022 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 9.48 MBLicence: CC BY

6 Citations
1 Article

Author correction: Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
Wang, W., Bale, S., Wei, J., Yalavarthi, B., Bhattacharyya, D., Yan, J. J., Abdala-Valencia, H., Xu, D., Sun, H., Marangoni, R. G., Herzog, E., Berdnikovs, S., Miller, S. D., Sawalha, A. H., Tsou, P.-S., Awaji, K., Yamashita, T., Sato, S., Asano, Y. & Tiruppathi, C. & 4 others, Yeldandi, A., Schock, B. C., Bhattacharyya, S. & Varga, J., 31 Jan 2023, (Early online date) In: Nature Communications. 14, 1, 1 p., 523.
Research output: Contribution to journal › Article › peer-review

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Wang, W., Bale, S., Wei, J., Yalavarthi, B., Bhattacharyya, D., Yan, J. J., Abdala-Valencia, H., Xu, D., Sun, H., Marangoni, R. G., 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, Article 6358. https://doi.org/10.1038/s41467-022-33767-y

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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.",

keywords = "Mice, Knockout, Receptors, Adiponectin - metabolism, Animals, Disease Models, Animal, Cells, Cultured, Ubiquitins - metabolism, Bleomycin, Fibrosis, Skin - pathology, Scleroderma, Systemic - metabolism, Signal Transduction - genetics, Transforming Growth Factor beta - metabolism, Mice, Fibroblasts - metabolism",

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 Marangoni, {Roberta G} and Erica Herzog and Sergejs Berdnikovs and Miller, {Stephen D} and Sawalha, {Amr H} and Pei-Suen Tsou 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",

year = "2022",

month = oct,

day = "26",

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

language = "English",

volume = "13",

journal = "Nature Communications",

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Wang, W, Bale, S, Wei, J, Yalavarthi, B, Bhattacharyya, D, Yan, JJ, Abdala-Valencia, H, Xu, D, Sun, H, Marangoni, RG, Herzog, E, Berdnikovs, S, Miller, SD, Sawalha, AH, Tsou, P-S, 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, 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 - Marangoni, Roberta G

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

PY - 2022/10/26

Y1 - 2022/10/26

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.

KW - Mice, Knockout

KW - Receptors, Adiponectin - metabolism

KW - Animals

KW - Disease Models, Animal

KW - Cells, Cultured

KW - Ubiquitins - metabolism

KW - Bleomycin

KW - Fibrosis

KW - Skin - pathology

KW - Scleroderma, Systemic - metabolism

KW - Signal Transduction - genetics

KW - Transforming Growth Factor beta - metabolism

KW - Mice

KW - Fibroblasts - metabolism

U2 - 10.1038/s41467-022-33767-y

DO - 10.1038/s41467-022-33767-y

M3 - Article

C2 - 36289219

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 6358

ER -

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

Abstract

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

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