Title | A protective Langerhans cell-keratinocyte axis that is dysfunctional in photosensitivity. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Shipman WD, Chyou S, Ramanathan A, Izmirly PM, Sharma S, Pannellini T, Dasoveanu DC, Qing X, Magro CM, Granstein RD, Lowes MA, Pamer EG, Kaplan DH, Salmon JE, Mehrara BJ, Young JW, Clancy RM, Blobel CP, Lu TT |
Journal | Sci Transl Med |
Volume | 10 |
Issue | 454 |
Date Published | 2018 08 15 |
ISSN | 1946-6242 |
Keywords | ADAM17 Protein, Animals, Apoptosis, Cytoprotection, Disease Models, Animal, Epidermis, ErbB Receptors, Humans, Keratinocytes, Langerhans Cells, Ligands, Lupus Erythematosus, Systemic, Mice, Inbred C57BL, Phosphorylation, Ultraviolet Rays |
Abstract | 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. |
DOI | 10.1126/scitranslmed.aap9527 |
Alternate Journal | Sci Transl Med |
PubMed ID | 30111646 |
PubMed Central ID | PMC6365282 |
Grant List | R01 AI079178 / AI / NIAID NIH HHS / United States R01 GM064750 / GM / NIGMS NIH HHS / United States T32 AR071302 / AR / NIAMS NIH HHS / United States S10 OD019986 / OD / NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
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