Objective

Psoriasis is a chronic inflammatory skin disease that is thought to affect ∼2% of the global population. Psoriasis has been associated with ∼30% increased risk of developing type 2 diabetes (T2D), with numerous studies reporting that psoriasis is an independent risk-factor for T2D, separate from underlying obesity. Separately, studies of skin-specific transgenic mice have reported altered whole-body glucose homeostasis in these models. These studies imply a direct role for skin inflammation and dysfunction in mediating the onset of T2D in psoriasis patients, potentially via the endocrine effects of the skin secretome on key metabolic tissues. We used a combination of in vivo and ex vivo mouse models and ex vivo human imiquimod (IMQ) models to investigate the effects of psoriasis-mediated changes in the skin secretome on whole-body metabolic function.

Methods

To induce psoriatic skin inflammation, mice were topically administered 75 mg of 5% IMQ cream (or Vaseline control) to a shaved dorsal region for 4 consecutive days. On day 5, mice were fasted for glucose and insulin tolerance testing, or sacrificed in the fed state with blood and tissues collected for analysis. To determine effects of the skin secretome, mouse skin was collected at day 5 from IMQ mice and cultured for 24 h. Conditioned media (CM) was collected and used 1:1 with fresh media to treat mouse explant subcutaneous adipose tissue (sAT) and isolated pancreatic islets. For human CM experiments, human skin was exposed to 5% IMQ cream for 20 min, ex vivo, to induce a psoriatic phenotype, then cultured for 24 h. CM was collected, combined 1:1 with fresh media and used to treat human sAT ex vivo. Markers of tissue inflammation and metabolic function were determined by qPCR. Beta cell function in isolated islets was measured by dynamic insulin secretion. Beta-cell proliferation was determined by measurement of Ki67 immunofluorescence histochemistry and BrDU uptake, whilst islet apoptosis was assessed by caspase 3/7 activity. All data is expressed as mean ± SEM.

Results

Topical treatment with IMQ induced a psoriatic-like phenotype in mouse skin, evidenced by thickening, erythema and inflammation of the skin. Topical IMQ treatment induced inflammation and signs of metabolic dysfunction in sub-cutaneous and epidydimal adipose tissue, liver, skeletal muscle and gut tissue. However, consistent with islet compensation and a pre-diabetic phenotype, IMQ mice displayed improved glucose tolerance, increased insulin and c-peptide response to glucose, and increased beta cell proliferation. Treatment of sAT with psoriatic mouse or human skin-CM replicated the in vivo phenotype, leading to increased inflammation and metabolic dysfunction in mouse and human sAT. Treatment of pancreatic islets with psoriatic mouse skin-CM induced increases in beta-proliferation and apoptosis, thus partially replicating the in vivo phenotype.

Conclusions

Psoriasis-like skin inflammation induces a pre-diabetic phenotype, characterised by tissue inflammation and markers of metabolic dysfunction, together with islet compensation in mice. The in vivo phenotype is partially replicated by exposure of sAT and pancreatic islets to psoriatic-skin conditioned media. These results support the hypothesis that psoriatic skin inflammation, potentially via the endocrine actions of the skin secretome, may constitute a novel pathophysiological pathway mediating the development of T2D.

中文翻译：

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银屑病皮肤炎症通过皮肤分泌组的内分泌作用诱发糖尿病前期表型。

客观的

牛皮癣是一种慢性炎症性皮肤病，据信影响全球约 2% 的人口。银屑病与 2 型糖尿病 (T2D) 的风险增加约 30% 相关，大量研究报告称，银屑病是 T2D 的独立危险因素，与潜在的肥胖不同。另外，对皮肤特异性转基因小鼠的研究报告了这些模型中全身葡萄糖稳态的改变。这些研究表明，皮肤炎症和功能障碍在介导银屑病患者 T2D 发病中发挥着直接作用，可能是通过皮肤分泌组对关键代谢组织的内分泌影响。我们结合使用体内和离体小鼠模型以及离体人咪喹莫特（IMQ）模型来研究银屑病介导的皮肤分泌组变化对全身代谢功能的影响。

方法

为了诱导银屑病皮肤炎症，连续 4 天给小鼠剃毛的背部区域局部施用 75 毫克 5% IMQ 乳膏（或凡士林对照）。第5天，小鼠禁食进行葡萄糖和胰岛素耐量测试，或在进食状态下处死小鼠并收集血液和组织用于分析。为了确定皮肤分泌组的影响，在第 5 天从 IMQ 小鼠收集小鼠皮肤并培养 24 小时。收集条件培养基 (CM) 并与新鲜培养基按 1:1 的比例使用来处理小鼠外植体皮下脂肪组织 (sAT) 和分离的胰岛。对于人类 CM 实验，将人类皮肤离体暴露于 5% IMQ 霜中 20 分钟，以诱导银屑病表型，然后培养 24 小时。收集CM，与新鲜培养基1:1混合，用于离体处理人sAT 。通过 qPCR 测定组织炎症和代谢功能的标志物。通过动态胰岛素分泌来测量分离胰岛中的β细胞功能。通过测量 Ki67 免疫荧光组织化学和 BrDU 摄取来确定 β 细胞增殖，同时通过 caspase 3/7 活性评估胰岛细胞凋亡。所有数据均表示为平均值±SEM。

结果

IMQ 局部治疗在小鼠皮肤中诱导了银屑病样表型，表现为皮肤增厚、红斑和炎症。局部 IMQ 治疗会引起皮下和附睾脂肪组织、肝脏、骨骼肌和肠道组织的炎症和代谢功能障碍的迹象。然而，与胰岛补偿和糖尿病前期表型一致，IMQ 小鼠表现出葡萄糖耐量改善、胰岛素和 C 肽对葡萄糖的反应增加以及 β 细胞增殖增加。用银屑病小鼠或人类皮肤CM治疗sAT复制了体内表型，导致小鼠和人类sAT炎症增加和代谢功能障碍。用银屑病小鼠皮肤CM治疗胰岛可诱导β-增殖和细胞凋亡增加，从而部分复制体内表型。

结论

银屑病样皮肤炎症会诱发糖尿病前期表型，其特征是组织炎症和代谢功能障碍标志物，以及小鼠的胰岛代偿。通过将 sAT 和胰岛暴露于银屑病皮肤条件培养基，可部分复制体内表型。这些结果支持这样的假设：银屑病皮肤炎症可能通过皮肤分泌组的内分泌作用，可能构成介导 T2D 发展的新病理生理学途径。