Journal of dermatological science · 2021
Polycyclic aromatic hydrocarbons regulate the pigmentation pathway and induce DNA damage responses in keratinocytes, a process driven by systemic immunity.
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Chan Tze Khee, Bramono Diah, Bourokba Nasrine, Krishna Vedula, Wang Siew Tein, Neo Boon Hoe, Lim Rebecca Y X, Kim Hyoju, Misra Namita, Lim Shawn, Betts Richard J
Аннотация
BACKGROUND: Urban pollution is correlated with an increased prevalence of skin pigmentation disorders, however the physiological processes underlying this association are unclear.
OBJECTIVES: To delineate the relationship between polycyclic aromatic hydrocarbons (PAHs), a key constituent of atmospheric pollution, and immunity/skin pigmentation pathways.
METHODS: We exposed peripheral blood mononuclear cells (PBMC) to PAHs and performed cytokines/chemokine profiling. We then examined the effect of immune activation on pigmentation by co-culturing PBMC and Benzo(a)pyrene (BaP) with reconstructed human pigmented epidermis (RHPE). To study the mechanism, we treated keratinocytes with conditioned medium from BaP-exposed PBMC and studied DNA damage responses, aryl hydrocarbon receptor (AhR) activation and pro-pigmentation factor, proopiomelanocortin (POMC) secretion.
RESULTS: PAHs induced up-regulation of inflammatory cytokines/chemokine in PBMC. Co-culturing of RHPE with PBMC+BaP resulted in increased melanin content and localization. BaP-conditioned medium significantly increased DNA damage, p53 stabilization, AhR activation and POMC secretion in keratinocytes. We found that IFNγ induced DNA damage, while TNFα and IL-8 potentiated POMC secretion in keratinocytes. Importantly, BaP-conditioned medium-induced DNA damage and POMC secretion is prevented by antioxidants vitamin E, vitamin C and sulforaphane, as well as the prototypical corticosteroid dexamethasone. Finally, vitamin C and sulforaphane enhanced the genome protective and depigmentation effects of dexamethasone, providing proof-of-concept for a combinatorial approach for the prevention and/or correction of PAH-induced pigment spots formation.
CONCLUSION: Our study reveals the importance of systemic immunity in regulating PAH-induced skin pigmentation, and provide a new keratinocyte DNA damage response mechanistic target for the prevention or reversal of pollution-associated skin pigmentation.
OBJECTIVES: To delineate the relationship between polycyclic aromatic hydrocarbons (PAHs), a key constituent of atmospheric pollution, and immunity/skin pigmentation pathways.
METHODS: We exposed peripheral blood mononuclear cells (PBMC) to PAHs and performed cytokines/chemokine profiling. We then examined the effect of immune activation on pigmentation by co-culturing PBMC and Benzo(a)pyrene (BaP) with reconstructed human pigmented epidermis (RHPE). To study the mechanism, we treated keratinocytes with conditioned medium from BaP-exposed PBMC and studied DNA damage responses, aryl hydrocarbon receptor (AhR) activation and pro-pigmentation factor, proopiomelanocortin (POMC) secretion.
RESULTS: PAHs induced up-regulation of inflammatory cytokines/chemokine in PBMC. Co-culturing of RHPE with PBMC+BaP resulted in increased melanin content and localization. BaP-conditioned medium significantly increased DNA damage, p53 stabilization, AhR activation and POMC secretion in keratinocytes. We found that IFNγ induced DNA damage, while TNFα and IL-8 potentiated POMC secretion in keratinocytes. Importantly, BaP-conditioned medium-induced DNA damage and POMC secretion is prevented by antioxidants vitamin E, vitamin C and sulforaphane, as well as the prototypical corticosteroid dexamethasone. Finally, vitamin C and sulforaphane enhanced the genome protective and depigmentation effects of dexamethasone, providing proof-of-concept for a combinatorial approach for the prevention and/or correction of PAH-induced pigment spots formation.
CONCLUSION: Our study reveals the importance of systemic immunity in regulating PAH-induced skin pigmentation, and provide a new keratinocyte DNA damage response mechanistic target for the prevention or reversal of pollution-associated skin pigmentation.
Предметные рубрики MeSH
Anti-Inflammatory AgentsAntioxidantsAscorbic AcidBenzo(a)pyreneCells, CulturedCoculture TechniquesCulture Media, ConditionedCytokinesDNA DamageDNA RepairDexamethasoneEpidermisHumansImmune System PhenomenaInterferon-gammaInterleukin-8IsothiocyanatesKeratinocytesLeukocytes, MononuclearMelaninsPolycyclic Aromatic HydrocarbonsPro-OpiomelanocortinReceptors, Aryl HydrocarbonSkin PigmentationSulfoxidesTumor Necrosis Factor-alphaVitamin E