Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2

Ciechomska, Marzena, O'Reilly, Steven, Przyborski, Stefan, Oakley, Fiona, Bogunia-Kubik, Katarzyna and van Laar, Jacob (2016) Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2. Arthritis & Rheumatology, 68 (6). pp. 1493-1504. ISSN 2326-5191

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Abstract

Objective - To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP-1) via Fra-2 (an activator protein 1 [AP-1] family member), a novel downstream mediator that promotes fibrogenesis.

Methods - AP-1 transcription factors and TIMP-1 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra-2 in the regulation of TIMP-1 following treatment with Toll-like receptor 8 (TLR-8) agonist was investigated using a luciferase activity assay and chromatin immunoprecipitation (ChIP) analysis. Expression of TIMP-1 and Fra-2 was determined in response to TLR-8 treatment and to different histone modifications, including 3′-deazaneplanocin (DZNep) and apicidin. Fibroblasts from healthy controls were cocultured with DZNep plus TLR-8–treated healthy control monocytes.

Results - Up-regulation of Fra-2 was detected in bleomycin-challenged mice and in skin biopsy samples from SSc patients. Enhanced expression of Fra-2 and TIMP-1 was correlated in SSc monocytes (P = 0.021). The expression of Fra-1 was significantly reduced (P = 0.037) in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR-8–stimulated monocytes from healthy controls and SSc patients. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Stimulation with DZNep plus TLR-8 enhanced Fra-2 and TIMP-1 expression in healthy control monocytes, whereas TLR-8 plus apicidin repressed Fra-2 and TIMP-1 expression. Finally, healthy control monocytes treated with DZNep plus TLR-8 induced strong production of α-smooth muscle actin in dermal fibroblasts, which was inhibited by TIMP-1–blocking antibody.

Conclusion - These data demonstrate a novel role of histone demethylation induced by DZNep on Fra-2–mediated TIMP-1 production by monocytes in the presence of TLR-8 agonist. This consequently orchestrates the transdifferentiation of fibroblasts, a key event in the pathogenesis of SSc.

Item Type:	Article
Subjects:	B100 Anatomy, Physiology and Pathology
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Becky Skoyles
Date Deposited:	24 Apr 2017 08:31
Last Modified:	12 Oct 2019 18:30
URI:	http://nrl.northumbria.ac.uk/id/eprint/30536

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