Objectives To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc).
Methods We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4.
Results Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role.
Conclusions PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.
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Handling editor Tore K Kvien
Contributors Design of the study: CM, CB, JHWD, GS. Acquisition of data: CM. Interpretation of data: CM, CB, JHWD. Manuscript preparation: CM, CB, JHWD. Provided essential material: CM, AR, CB,CB, RW, NK.
Funding Grant support was provided by the Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsföderung (ELAN), grants J29, A57 and A64 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen and grants DI 1537/5–1, DI 1537/7–1, DI 1537/8–1, DI 1537/9–1, DI 1537/11–1, DI 1537/11–1, AK 144/2–1 and BE 5191/1–1 from the Deutsche Forschungsgemeinschaft. In addition, the study was supported by grant 2013.056.1 of the Wilhelm-Sander-Foundation, grant 2014_A47 of the Else-Kröner-Fresenius-Foundation, and a Career Support Award of Medicine of the Ernst Jung Foundation.
Competing interests JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GlaxoSmithKline (GSK), Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB. JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, Novartis, Sanofi-Aventis, UCB. JHWD is stock owner of 4D Science.
Ethics approval FAU Erlangen-Nuremberg.
Provenance and peer review Not commissioned; externally peer reviewed.
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