UV-mediated and mitochondrial stress responses in the pathogenesis of cutaneous lupus erythematosus

• Applicant: Dr. Benjamin Klein
• Subject Area: Dermatology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504540937

Cutaneous lupus erythematosus (CLE) represents a rare autoimmune disease, characterized by strong photosensitivity. Ultraviolet (UV) radiation is able to cause flare-ups of cutaneous and systemic disease. Epidermal derived interferon κ and other type 1 interferons (IFN) were identified as important cytokines in the pathogenesis of CLE after UV, while the precise mechanisms of induction are still poorly understood. Upon UV light, keratinocytes show DNA damage such as oxidized bases and activated DNA damage response. Oxidized mtDNA was shown to be a strong activator of type I IFN responses in neutrophils of SLE patients. The role of mitochondrial stress in keratinocytes for immune cell recruitment warrants further investigation. In this study, we aim to further identify the dysregulated mechanisms in lupus keratinocytes that contribute to increased type I IFN production and stimulation of the local and systemic immune system after UV exposure. Initially, DNA damage, DNA damage response, and secretion of IFNκ after UV exposure in lupus keratinocytes are determined. Further, we analyze the release of keratinocyte-derived extracellular vesicles and mitochondrial antigen upon UV exposition as well as the response to enhanced mitochondrial stress. These experiments will clarify which pathways are required for IFNκ and IFNβ production. As Type I IFNs act via activation of the JAK/STAT-pathway, a targeted approach represents the use of JAK-inhibitors (JAKi). Therefore, the project additionally aims to clarify, how JAKi may have a protective effect on photosensitivity. To investigate this aspect, multiome studies including single cell sequencing and spatially resolved transcriptomics will be performed in skin cells obtained from lupus patients previously treated with JAKi and UV. By identifying signaling pathways in the development of cutaneous lupus erythematosus, therapeutic approaches may be derived to impact the future treatment of lupus patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Joanne Michelle Kahlenberg, Ph.D.