Ciechomska, M. and O'Reilly, S. and Przyborski, S. and Oakley, F. and Bogunia-Kubik, K. and van Laar, J.M. (2016) 'Histone demethylation and toll‐like receptor 8–dependent cross‐talk in monocytes promotes transdifferentiation of fibroblasts in systemic sclerosis via Fra‐2.', Arthritis and rheumatology., 68 (6). pp. 1493-1504.
Objectives: To investigate whether epigenetic changes can modulate monocytes to produce tissue-inhibitor of metalloproteinase-1 (TIMP-1) via Fra2 (AP-1 family member), a novel downstream mediator promoting fibrogenesis. Methods: AP-1 transcription factors and TIMP-1 expression was measured in monocytes from systemic sclerosis (SSc) patients and healthy controls (HC). Involvement of Fra2 in the regulation of TIMP-1 following TLR8 agonist treatment was investigated using luciferase activity assay and ChIP analysis. Expression of TIMP-1 and Fra2 was determined in response to TLR8 treatment and different histone modifications including 3'deazaneplanocin (DZNep) and apicidin. HC fibroblasts were co-cultured with DZNep plus TLR8-treated HC monocytes. Results: Upregulation of Fra2 was detected in bleomycin-challenged mice and SSc skin biopsies. Enhanced expression of Fra2 and TIMP-1 was correlated in SSc monocytes (p=0.021). The expression of Fra1 was significantly (p=0.037) reduced in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR8 stimulated HC and SSc monocytes. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Combination of DZNep plus TLR8 enhanced Fra2 and TIMP-1 expression in HC monocytes, whereas TLR8 plus apicidin repressed Fra2 and TIMP-1 expression. Finally, DZNep plus TLR8-treated HC monocytes induced strong production of α-SMA in dermal fibroblasts, which was inhibited by TIMP-1 blocking antibody. Conclusions: These data demonstrate a novel role of histone demethylation induced by DZNep on Fra2-mediated TIMP-1 production by monocytes in the presence of TLR8 agonist. This consequently orchestrates fibroblasts' trans-differentiation, a key event in the pathogenesis of SSc.
|Keywords:||Systemic sclerosis, Monocytes, TLR signaling, Epigenetics, TIMP-1.|
|Full text:||(AM) Accepted Manuscript|
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|Publisher Web site:||https://doi.org/10.1002/art.39602|
|Publisher statement:||This is the accepted version of the following article: Ciechomska, M., O'Reilly, S., Przyborski, S., Oakley, F., Bogunia-Kubik, K. & van Laar, J.M. (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): 1493-1504, which has been published in final form at https://doi.org/10.1002/art.39602. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.|
|Date accepted:||14 January 2016|
|Date deposited:||09 February 2016|
|Date of first online publication:||26 May 2016|
|Date first made open access:||26 May 2017|
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