Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis
Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis
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DOI：
10.1038/s41420-020-0245-8
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发表时间：
2020-03-04
影响因子：
7
通讯作者：
Nakahara, Takeshi
中科院分区：
文献类型：
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作者：
Tsuji, Gaku;Hashimoto-Hachiya, Akiko;Nakahara, Takeshi
银屑病是一种全身性炎症性疾病，与包括2型糖尿病（T2 DM）在内的合并症显著相关。二甲双胍被用作治疗T2 DM的一线药物。尽管据报道二甲双胍通过T2 DM患者巨噬细胞中的NLRP 3炎性小体抑制成熟IL-1 β分泌，但仍不清楚其是否影响银屑病的皮肤炎症。为了测试这一点，我们分析了正常人表皮角质形成细胞（NHEK），一种主要的皮肤成分，刺激银屑病发展的关键介质，TNF-α和IL-17 A。这种刺激诱导了pro-IL-1 β mRNA和蛋白水平的上调，随后诱导了成熟的IL-1 β分泌，二甲双胍处理可抑制IL-1 β分泌。为了进一步揭示相关机制，我们研究了二甲双胍治疗如何影响TNF-α和IL-17 A刺激激活的NLRP 3炎性小体。我们发现，这种治疗下调了caspase-1的表达，这是NLRP 3炎性体的关键介质。此外，AMPK和SIRT 1的抑制剂消除了二甲双胍治疗诱导的caspase-1的下调，表明AMPK和SIRT 1对NHEK中NLRP 3炎性体的抑制作用至关重要。由于IL-1 β刺激诱导NHEK中IL-36 γ、CXCL 1、CXCL 2、CCL 20、S100 A7、S100 A8和S100 A9 mRNA和蛋白水平上调，我们检查了二甲双胍治疗是否影响此类基因表达。二甲双胍处理抑制TNF-α和IL-17 A刺激诱导的IL-36 γ、CXCL 1、CXCL 2、CCL 20、S100 A7、S100 A8和S100 A9 mRNA和蛋白水平的上调。最后，我们在咪喹莫特诱导的小鼠银屑病模型中检查二甲双胍给药是否影响银屑病的发展。口服二甲双胍治疗显著降低耳厚度、表皮增生和炎性细胞浸润。二甲双胍治疗下表皮中的细胞因子谱显示，与对照水平相比，IL-1 β、Cxcl 1、Cxcl 2、S100 a7、S100 a8和S100 A9 mRNA水平下调。这些结果表明，二甲双胍给药可预防体内银屑病的发生。总的来说，我们的研究结果表明二甲双胍介导的抗银屑病作用对皮肤有治疗银屑病的T2 DM患者的潜力。
Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1 beta secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-alpha and IL-17A. This stimulation induced the upregulation of pro-IL-1 beta mRNA and protein levels, and subsequently mature IL-1 beta secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-alpha and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogated the downregulation of caspase-1 induced by metformin treatment, indicating that AMPK and SIRT1 are essential for the inhibitory effect on NLRP3 inflammasome in NHEKs. As IL-1 beta stimulation induced upregulation of IL-36 gamma, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels in NHEKs, we examined whether metformin treatment affects such gene expression. Metformin treatment inhibited upregulation of IL-36 gamma, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-alpha and IL-17A stimulation. Finally, we examined whether metformin administration affected psoriasis development in an imiquimod-induced mouse psoriasis model. Oral metformin treatment significantly decreased ear thickness, epidermal hyperplasia and inflammatory cell infiltration. A cytokine profile in the epidermis under metformin treatment showed that IL-1 beta, Cxcl1, Cxcl2, S100a7, S100a8 and S100A9 mRNA levels were downregulated compared with control levels. These results indicate that metformin administration prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients.