A20 ameliorates advanced glycation end products-induced melanogenesis by inhibiting NLRP3 inflammasome activation in human dermal fibroblasts

Mengyao Wang , Xianyin Huang , Mengting Ouyang , Jingjing Lan, Jingqian Huang, Hongpeng Li, Wei Lai, Yifeng Gao, Qingfang Xu
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Abstract

Background

Advanced glycation end products (AGEs) promote melanogenesis through activating NLRP3 inflammasome in fibroblasts. Although A20 has been highlighted to inhibit NLRP3 inflammasome activation, its roles and mechanisms remain elusive in photoaging-associated pigmentation.

Objectives

To determine the significance of fibroblast A20 in AGEs-induced NLRP3 inflammasome activation and pigmentation.

Methods

The correlation between A20 and AGEs or melanin was studied in sun-exposed skin and lesions of melasma and solar lentigo. We then investigated A20 level in AGEs-treated fibroblast and the effect of fibroblast A20 overexpression or knockdown on AGEs-BSA-induced NLRP3 inflammasome activation and pigmentation, respectively. Finally, the severity of NLRP3 inflammasome activation and pigmentation was evaluated after mice were injected intradermally with A20-overexpression adeno-associated virus and AGEs-BSA.

Results

Dermal A20 expression was decreased and exhibited negative correlation with either dermal AGEs deposition or epidermal melanin level in sun-exposed skin and pigmentary lesions. Moreover, both AGEs-BSA and AGEs-collagen robustly decreased A20 expression via binding to RAGE in fibroblasts. Further, A20 overexpression or depletion significantly decreased or augmented AGEs-BSA-induced activation of NF-κB pathway and NLRP3 inflammasome and IL-18 production and secretion in fibroblasts, respectively. Importantly, fibroblast A20 potently repressed AGEs-BSA-stimulated melanin content,tyrosinase activity,and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes. Particularly, fibroblast A20 significantly abrogated AGEs-BSA-promoted melanogenesis in ex vivo skin and mouse models. Additionally, fibroblast A20 inhibited AGEs-BSA-activated MAPKs in melanocytes and the epidermis of ex vivo skin.

Conclusions

Fibroblast A20 suppresses AGEs-stimulate melanogenesis in photoaging-associated hyperpigmentation disorders by inhibiting NLRP3 inflammasome activation.

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A20通过抑制人真皮成纤维细胞中NLRP3炎症小体的激活,改善晚期糖基化终产物诱导的黑色素生成。
背景:晚期糖基化终产物(AGEs)通过激活成纤维细胞中的NLRP3炎症小体促进黑色素生成。尽管A20已被强调可抑制NLRP3炎症小体激活,但其在光老化相关色素沉着中的作用和机制仍然难以捉摸。目的:确定成纤维细胞A20在AGEs诱导的NLRP3炎症小体活化和色素沉着中的意义。方法:对日光照射皮肤及黄褐斑、雀斑病变中A20与AGEs或黑色素的相关性进行研究。然后,我们分别研究了AGEs处理的成纤维细胞中A20水平以及成纤维细胞A20过表达或敲低对AGEs-BSA诱导的NLRP3炎症小体激活和色素沉着的影响。最后,在小鼠皮内注射A20过表达腺相关病毒和AGEs-BSA后,评估NLRP3炎症小体激活和色素沉着的严重程度。结果:皮肤A20表达降低,并与暴露在阳光下的皮肤和色素病变中的真皮AGEs沉积或表皮黑色素水平呈负相关。此外,AGEs BSA和AGEs胶原都通过与成纤维细胞中的RAGE结合而显著降低A20的表达。此外,A20过表达或缺失分别显著降低或增强了成纤维细胞中AGEs-BSA诱导的NF-κB通路和NLRP3炎症小体的激活以及IL-18的产生和分泌。重要的是,成纤维细胞A20有效抑制AGEs-BSA刺激的黑色素含量、酪氨酸酶活性以及黑色素细胞中小眼相关转录因子和酪氨酸酶的表达。特别地,在离体皮肤和小鼠模型中,成纤维细胞A20显著消除AGEs-BSA促进黑色素生成。此外,成纤维细胞A20抑制黑素细胞和离体皮肤表皮中的AGEs-BSA激活的MAPKs。结论:成纤维细胞A20通过抑制NLRP3炎症小体激活,抑制AGEs刺激光老化相关色素沉着障碍中的黑色素生成。
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