ABSTRACT
BACKGROUND: Advanced glycation end products (AGEs) promote melanogenesis through activating NLRP3 inï¬ammasome in fibroblasts. Although A20 has been highlighted to inhibit NLRP3 inï¬ammasome 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 contentï¼tyrosinase activityï¼and 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 inï¬ammasome activation.
Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Humans , Animals , Mice , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Signal Transduction , Glycation End Products, Advanced/metabolism , Melanins/metabolism , Monophenol Monooxygenase/metabolism , Fibroblasts/metabolismABSTRACT
BACKGROUND: Both epidemiological and clinical studies have suggested the comorbidity between cutaneous melanoma (CM) and obesity-related physical traits. However, it remains unclear about their shared genetic architecture. OBJECTIVE: To determine the shared genetic architecture between CM and obesity-related physical traits through conditional false discovery rate (cFDR) analysis. METHOD: Quantile-quantile plots were firstly built to assess the pleiotropic enrichment of shared single nucleotide polymorphisms between CM and each trait. Then, cFDR and conjunctional cFDR (ccFDR) were used to identify the shared risk loci between CM and each trait. Moreover, the functional evaluation of shared risk genes was carried out through analyses of expression quantitative trait loci (eQTL), Kyoto Encyclopedia of Genes and Genomes and gene ontology, respectively. Finally, single-cell sequence analysis was performed to locate the expression of eQTL-mapped genes in tissues. RESULTS: Successive pleiotropic enrichment was found between CM and 5 obesity-related traits or height. 24 shared risk loci were identified between CM and 13 traits except appendicular lean mass using ccFDR analysis, with 17 novel and 4 validated loci. The functions of ccFDR-identified and eQTL-mapped genes were revealed to be mainly involved in cellular senescence, proliferation, meiotic nuclear division, cell cycle, and the metabolism of lipid, cholesterol and glucose. Single-cell sequence analysis showed that keratinocytes contribute to the occurrence and aggressiveness of CM through secreting paracrine cytokines. CONCLUSION: Our findings demonstrate the significant genetic correlation between CM and obesity-related physical traits, which may provide a novel genetical basis for the pathogenesis and treatment of CM.
