Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, China.
Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, China; State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
J Photochem Photobiol B. 2024 Aug;257:112948. doi: 10.1016/j.jphotobiol.2024.112948. Epub 2024 May 29.
Autophagy participates in the regulation of ferroptosis. Among numerous autophagy-related genes (ATGs), ATG5 plays a pivotal role in ferroptosis. However, how ATG5-mediated ferroptosis functions in UVB-induced skin inflammation is still unclear. In this study, we unveil that the core ferroptosis inhibitor GPX4 is significantly decreased in human skin tissue exposed to sunlight. We report that ATG5 deletion in mouse keratinocytes strongly protects against UVB-induced keratinocyte ferroptosis and skin inflammation. Mechanistically, ATG5 promotes the autophagy-dependent degradation of GPX4 in UVB-exposed keratinocytes, which leads to UVB-induced keratinocyte ferroptosis. Furthermore, we find that IFN-γ secreted by ferroptotic keratinocytes facilitates the M1 polarization of macrophages, which results in the exacerbation of UVB-induced skin inflammation. Together, our data indicate that ATG5 exacerbates UVB-induced keratinocyte ferroptosis in the epidermis, which subsequently gives rise to the secretion of IFN-γ and M1 polarization. Our study provides novel evidence that targeting ATG5 may serve as a potential therapeutic strategy for the amelioration of UVB-caused skin damage.
自噬参与铁死亡的调控。在众多自噬相关基因（ATGs）中，ATG5 在铁死亡中发挥关键作用。然而，ATG5 介导的铁死亡如何在 UVB 诱导的皮肤炎症中发挥作用尚不清楚。在本研究中，我们揭示了暴露于阳光下的人皮肤组织中核心铁死亡抑制剂 GPX4 显著减少。我们报告说，在小鼠角质细胞中缺失 ATG5 可强烈防止 UVB 诱导的角质细胞铁死亡和皮肤炎症。在机制上，ATG5 促进了 UVB 暴露的角质细胞中 GPX4 的自噬依赖性降解，从而导致 UVB 诱导的角质细胞铁死亡。此外，我们发现铁死亡的角质细胞分泌的 IFN-γ促进了巨噬细胞的 M1 极化，导致了 UVB 诱导的皮肤炎症加重。总之，我们的数据表明 ATG5 加剧了表皮中 UVB 诱导的角质细胞铁死亡，随后导致 IFN-γ的分泌和 M1 极化。我们的研究提供了新的证据，表明靶向 ATG5 可能是改善 UVB 引起的皮肤损伤的潜在治疗策略。
