ZnO NPs delay the recovery of psoriasis-like skin lesions through promoting inflammation and keratinocyte apoptosis via nuclear translocation of phosphorylated NF-κB p65 and cysteine deficiency

Abstract Background This study aimed to confirm the safety and risk of applying zinc oxide nanoparticles (ZnO NPs) to pathological skin, such as psoriasis-like skin. The majority of previous studies confirmed the safety of applying ZnO NPs to normal skin. However, we know very little about the risks of using sunscreen, cosmetics and topical drugs containing ZnO NPs for individuals with skin diseases. In addition, some studies claimed that ZnO NPs can penetrate normal or pathological skin, and ZnO NPs have frequently been reported to have proinflammatory and lethal effects in vitro. Therefore, it is necessary to evaluate the safety of applying ZnO NPs to pathological skin. Results ZnO NPs passed through gaps between keratinocytes and entered stratum basale of epidermis and dermis in imiquimod (IMQ)-induced psoriasis-like skin lesions. Application of a ZnO NP-containing suspension for 3 connective days delayed the healing of the epidermal barrier; increased the expression levels of inflammatory cytokines; promoted keratinocyte apoptosis and disturbed redox homeostasis. In vitro, ZnO NPs promoted TNF-α, IL-1β and IL-6 secretion and apoptosis of recombinant-human-TNF-α-stimulated HaCaT cells. NF-κB, ERK, p38 and JNK inhibitors blocked ZnO NP-induced inflammation. JSH-23, an inhibitor of the nuclear translocation of p-NF-κB p65, and NAC, an acetylated precursor of L-cysteine, not only inhibited the ZnO NP-induced inflammation but also inhibited apoptosis and cysteine deficiency. Neither erastin nor RSL3 induced p-NF-κB p65 nuclear translocation, but they did reduce cysteine biosynthesis. Additionally, ferropstatin-1, an inhibitor of lipid peroxidation, partially rescued ZnO NP-induced decreases in cell viability and cysteine content. Conclusions ZnO NPs delay the recovery of psoriasis-like skin lesions through promoting inflammation and keratinocyte apoptosis via the nuclear translocation of phosphorylated NF-κB p65 and cysteine deficiency. This work reminds the public that ZnO NPs are not safe for pathological skin, especially in inflammatory skin diseases such as psoriasis, and has revealed a partial mechanism by which ZnO NPs delay the recovery of pathological skin, promoting the appropriate use of ZnO NPs.