Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages
Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages
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DOI：
10.1136/annrheumdis-2016-210189
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发表时间：
2017-06-01
影响因子：
27.4
通讯作者：
Beyer, Christian
中科院分区：
文献类型：
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作者：
Maier, Christiane;Ramming, Andreas;Beyer, Christian
目的探讨抑制磷酸二酯酶4 （PDE4）在系统性硬化症（SSc）临床前模型中的疾病改善作用。方法研究PDE4抑制在博莱霉素诱导的皮肤纤维化的预防和治疗模型、拓扑异构酶小鼠模型以及硬化性慢性移植物抗宿主病模型中的作用。为了更好地了解PDE4阻断在SSc临床前模型中的作用模式，我们研究了健康个体和弥漫性皮肤SSc患者成纤维细胞和巨噬细胞中与纤维化相关的介质对PDE4阻断的影响。结果罗利普兰和阿普雷米司特特异性抑制PDE4在博莱霉素诱导的皮肤纤维化模型、拓扑异构酶I小鼠模型和小鼠慢性硬皮病移植抗宿主病中具有有效的抗纤维化作用。成纤维细胞不是PDE4阻断抗纤维化作用的直接靶点。PDE4阻断后病变皮肤白细胞浸润减少，提示其免疫介导机制。进一步分析发现，PDE4抑制抑制M2巨噬细胞的分化和几种促纤维化细胞因子的释放，导致成纤维细胞活化和胶原释放减少。在这些促纤维化介质中，白细胞介素-6似乎起着核心作用。结论PDE4抑制可降低M2巨噬细胞的炎症细胞活性和促纤维化细胞因子的释放，导致成纤维细胞活化和胶原蛋白释放降低。重要的是，阿普雷米司特已经被批准用于治疗银屑病和银屑病关节炎。因此，PDE4抑制剂可能会进一步发展成为SSc患者潜在的抗纤维化治疗药物。我们的研究结果表明，特别是炎症驱动性纤维化患者可能受益于PDE4阻断。
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.