Department of Dermatology, Shaanxi Provincial Institute of Dermatology and Venereology, Xi'an, 710003, Shaanxi, China.
Department of Dermatology, Xi'an Central Hospital, Xi'an, 710003, Shaanxi, China.
Biochem Biophys Res Commun. 2022 Oct 1;623:1-8. doi: 10.1016/j.bbrc.2022.07.041. Epub 2022 Jul 14.
More and more studies have shown that ferroptosis is closely related to the progression of various diseases, but the significance of ferroptosis in psoriasis is still rarely explored. The detection of plasma and psoriatic lesions found that the contents of MDA and ROS were significantly increased, while the contents of SOD and GSH were significantly decreased, and the trend of increase or decrease in patients with progressive psoriasis was more obvious. The expression of ACSL4, a key regulator of ferroptosis, was significantly increased in psoriatic lesions and further up-regulated in patients with progressive psoriasis. ACSL4 expression was positively correlated with PASI score and the expression levels of inflammatory cytokines (TNF-α, IL-6, IL-8 and IL-17a), and linear regression analysis showed that high expression of ACSL4 in psoriatic lesions was associated with higher PASI score. Both ferroptosis inducer Erastin and IFN-γ/TNF-α significantly induced ferroptosis, inhibited keratinocyte viability, promoted the accumulation of MDA, ROS and Fe, and enhanced ACSL4, TNF-α, IL-6 and IL-8 expression. When ferroptosis inhibitor Ferrostatin-1 was added to inhibit ferroptosis, the up-regulation trends of MDA, ROS, Fe, ACSL4, TNF-α, IL-6 and IL-8 were significantly inhibited, and inhibition of ACSL4 expression also had a similar effect. Apoptosis inhibitor Z-VAD-FMK could also attenuate the pro-inflammatory effect of IFN-γ/TNF-α, and Fer-1 plus Z-VAD-FMK further inhibited the expression of inflammatory cytokines. Thus, ferroptosis is significantly activated during the progression of psoriasis and promotes inflammatory responses by upregulating ACSL4 expression. This discovery will provide new targets for clinical detection, prevention and treatment of psoriasis.
越来越多的研究表明，铁死亡与各种疾病的进展密切相关，但铁死亡在银屑病中的意义仍很少被探索。对血浆和银屑病皮损的检测发现，MDA 和 ROS 的含量明显增加，而 SOD 和 GSH 的含量明显降低，进展性银屑病患者的增加或减少趋势更为明显。铁死亡关键调节因子 ACSL4 在银屑病皮损中的表达明显增加，在进展性银屑病患者中进一步上调。ACSL4 的表达与 PASI 评分和炎症细胞因子（TNF-α、IL-6、IL-8 和 IL-17a）的表达水平呈正相关，线性回归分析显示，银屑病皮损中 ACSL4 的高表达与 PASI 评分较高有关。铁死亡诱导剂 Erastin 和 IFN-γ/TNF-α 均能显著诱导铁死亡，抑制角质形成细胞活力，促进 MDA、ROS 和 Fe 的积累，并增强 ACSL4、TNF-α、IL-6 和 IL-8 的表达。当加入铁死亡抑制剂 Ferrostatin-1 抑制铁死亡时，MDA、ROS、Fe、ACSL4、TNF-α、IL-6 和 IL-8 的上调趋势明显受到抑制，抑制 ACSL4 的表达也有类似的效果。凋亡抑制剂 Z-VAD-FMK 也可以减弱 IFN-γ/TNF-α 的促炎作用，Fer-1 加 Z-VAD-FMK 进一步抑制了炎症细胞因子的表达。因此，银屑病进展过程中明显激活了铁死亡，通过上调 ACSL4 的表达促进炎症反应。这一发现将为银屑病的临床检测、预防和治疗提供新的靶点。
