A protective Langerhans cell-keratinocyte axis that is dysfunctional in photosensitivity

• Published in: Science translational medicine 2018-08, Vol.10 (454)
• Main Authors: Shipman, William D, Chyou, Susan, Ramanathan, Anusha, Izmirly, Peter M, Sharma, Sneh, Pannellini, Tania, Dasoveanu, Dragos C, Qing, Xiaoping, Magro, Cynthia M, Granstein, Richard D, Lowes, Michelle A, Pamer, Eric G, Kaplan, Daniel H, Salmon, Jane E, Mehrara, Babak J, Young, James W, Clancy, Robert M, Blobel, Carl P, Lu, Theresa T
• Format: Article
• Language: English
• Subjects: ADAM17 Protein - metabolism; Animals; Apoptosis; Apoptosis - radiation effects; Cytoprotection - radiation effects; Diphtheria; Diphtheria toxin; Disease Models, Animal; Epidermal growth factor; Epidermal growth factor receptors; Epidermis - metabolism; Epidermis - radiation effects; ErbB Receptors - metabolism; Humans; Keratinocytes; Keratinocytes - cytology; Keratinocytes - radiation effects; Langerhans Cells - cytology; Langerhans Cells - radiation effects; Ligands; Lupus Erythematosus, Systemic - pathology; Metalloproteinase; Mice, Inbred C57BL; Phosphorylation; Phosphorylation - radiation effects; Photosensitivity; Skin; Systemic lupus erythematosus; Ultraviolet radiation; Ultraviolet Rays
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aap9527

Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.