811 UVB initiates skin inflammation by promoting keratinocyte ferroptosis

Abstract

Epidermis, composed primarily of the keratinocytes, is subjected to ultraviolet radiation (UVR)-induced oxidative and genotoxic stresses. That the keratinocytes are the initial source of pro-inflammatory mediators in the skin after UVR exposure has been well established. Ultraviolet B radiation (UVB) is a strong initiator of cutaneous inflammation, and contributes to the etiology and the exacerbation of several cutaneous diseases, such as lupus erythematosus. However, the mechanism of UVB-induced inflammation in the skin remains unclear. Utilizing primary human keratinocytes and human epidermal explants, we found that ferroptosis, a type of non-apoptotic programmed cell death associated with an excessive phospholipid peroxidation, is activated in the keratinocytes after UVB exposure. We further found that keratinocyte susceptibility to UVB-induced ferroptosis is dictated by the extent of lipid peroxidation and the dysregulation of glutathione system. Ferroptosis inhibition prevented HMGB1 release from the keratinocytes and protected UVB-irradiated skin from inflammation. While apoptosis and pyroptosis were also detectable in the keratinocytes after UVB exposure, we determined that ferroptosis of the keratinocytes plays a dominant role in initiating UVB-induced cutaneous inflammation. Our findings have significant implications for the prevention and treatment of a wide range of skin diseases fostered by UVB-induced inflammation.