Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure
Kavita Vats,
Oleg Kruglov,
Alicia Mizes,
Svetlana N. Samovich,
Andrew A. Amoscato,
Vladimir A. Tyurin,
Yulia Y. Tyurina,
Valerian E. Kagan,
Yuri L. Bunimovich
Affiliations
Kavita Vats
Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Oleg Kruglov
Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Alicia Mizes
School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Svetlana N. Samovich
Center for Free Radical and Antioxidant Health, Department of Environmental Health and Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Andrew A. Amoscato
Center for Free Radical and Antioxidant Health, Department of Environmental Health and Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Vladimir A. Tyurin
Center for Free Radical and Antioxidant Health, Department of Environmental Health and Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Yulia Y. Tyurina
Center for Free Radical and Antioxidant Health, Department of Environmental Health and Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Valerian E. Kagan
Center for Free Radical and Antioxidant Health, Department of Environmental Health and Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Yuri L. Bunimovich
Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Hillman Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA; Corresponding author. Department of Dermatology, University of Pittsburgh Medical Center, E1157 Thomas E. Starzl Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
The ultraviolet B radiation (UVB) causes skin inflammation, which contributes to the causality and the exacerbation of a number of cutaneous diseases. However, the mechanism of UVB-driven inflammation in the skin remains poorly understood. We show that ferroptosis, a non-apoptotic programmed cell death pathway that is promoted by an excessive phospholipid peroxidation, is activated in the epidermal keratinocytes after their exposure to UVB. The susceptibility of the keratinocytes to UVB-induced ferroptosis depends on the extent of pro-ferroptosis death signal generation and the dysregulation of the glutathione system. Inhibition of ferroptosis prevents the release of HMGB1 from the human epidermal keratinocytes, and blocks necroinflammation in the UVB-irradiated mouse skin. We show that while apoptosis and pyroptosis are also detectable in the keratinocytes after UVB exposure, ferroptosis plays a significant role in initiating UVB-induced inflammation in the skin. Our results have important implications for the prevention and the treatment of a broad range of skin diseases which are fostered by UVB-induced inflammation.
