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A20 governs fibrosis susceptibility in bleomycin-induced mouse scleroderma model

ABSTRACT: In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding A20 are also associated with systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to fibrosis in SSc, and which cell types drive disease due to SSc-specific genetic alterations. We characterized the expression and function of A20, and its negative transcriptional regulator DREAM, in patient with SSc. We found that levels of A20 were significantly reduced in SSc skin and lung biopsies, while DREAM was elevated and showed anti-correlation with A20. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulated major pathological and genomic features of SSc, whereas DREAM-null mice showed elevated A20 expression and were protected from fibrosis. In fibroblasts, A20 mitigated ex vivo profibrotic responses. An anti-fibrotic small molecule targeting the adiponectin receptors stimulated A20 expression in vitro in wildtype but not A20-deficient fibroblasts, and in bleomycin-treated mice. Thus, A20 has a novel function in negative regulation of fibroblast responses, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc, suggesting that A20 and DREAM represent novel druggable targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE194380 | GEO | 2022/02/01

REPOSITORIES: GEO

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Ubiquitin Proteomics Analysis of Systemic Sclerosis Lung Fibroblasts with or without KLHL42 knockdown

Project description:Systemic scleroderma (SSc) is an autoimmune disease which results in fibrotic production in the lung. Resultant SSC-pulmonary fibrosis is the main cause of mortality among SSc patients. From high throughput RNAi screening, we uncovered the ubiquitin E3 ligase KLHL42 as a potential pro-fibrotic mediator of TGFb-dependent fibrotic signaling in primary SSc lung fibroblasts. In this analysis, we sought to uncover putative substrates for KLHL42 by comparing SSc lung fibroblasts with control or KLHL42 siRNA prior to TGFb-treatment, lysis, and TUBE precipitation. The resultant pull-down was analyzed with LC-MS/MS.

2020-01-14 | MSV000084800 | MassIVE

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Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 33 HA20 patients, we show that heterozygous TNFAIP3 loss skews immune repertoires towards lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas.

2023-07-28 | E-MTAB-12491 | biostudies-arrayexpress

Gene expression profiles of CEBPβ-overexpressed alveolar macrophages after A20-Ad treatment

Project description:Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases.

2018-10-01 | GSE117690 | GEO

A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors

Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). Single-cell sequencing reveals “pre-lymphoma” transcription signatures in lymphocytes of HA20 patients.

2023-07-12 | E-MTAB-12485 | biostudies-arrayexpress

Effect of A20 deletion in a retroviral mouse model of AML

Project description:We show that AML patients who experience induction failure have elevated expression of the NF-kB target gene TNFAIP3/A20 and impaired necroptotic cell death, leading to a worse prognosis with chemotherapy. A20High AML samples display resistance to anthracyclines, while A20Low AML samples show sensitivity. Loss of A20 in AML cells restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, our studies revealed that A20 plays a critical role in AML development as deletion or knockdown of A20 effectively suppresses leukemic cells by mediating spontaneous necroptosis. A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML cells. These findings suggest that NF-kB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML. The data contained here provide a platform in which to examine the effects of A20 loss in a retroviral mouse model of AML.

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A20 IN MARGINAL ZONE LYMPHOMAS

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2009-04-01 | E-GEOD-13989 | biostudies-arrayexpress

Transcriptional responses to TNF-alpha in germline A20 haploinsufficiency

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2020-02-20 | GSE95078 | GEO

Gene expression profiles of alveolar macrophages isolated from wild type (WT) and A20 conditional knockout mice after BLM exposure

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2023-10-28 | GSE237064 | GEO

A20 IN MARGINAL ZONE LYMPHOMAS

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