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- Title
A protective Langerhans cell--keratinocyte axis that is dysfunctional in photosensitivity.
- 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.
- Abstract
Langerhans cells limit ultraviolet radiation–induced keratinocyte apoptosis and skin injury, and this axis is dysfunctional in lupus photosensitivity. Abrogating keratinocyte apoptosis in lupus: Lupus patients can experience photosensitivity as manifested by joint pain, fatigue, and skin rashes. To better understand the mechanisms behind this photosensitivity, Shipman et al. examined patient skin samples and mouse models of lupus. They saw that, in healthy mice and human skin exposed to ultraviolet radiation, Langerhans cells protected keratinocytes from apoptosis through a mechanism involving the metalloproteinase ADAM17 and EGFR ligands. In the lupus mice and patient samples, the Langerhans cells were unable to do this. Stimulating EGFR in the skin may bring relief to photosensitive lupus patients. 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.
- Subjects
LANGERHANS cells; PHOTOSENSITIVITY disorders; KERATINOCYTES; ULTRAVIOLET radiation; EPIDERMAL growth factor receptors; DISINTEGRINS; METALLOPROTEINASES
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 454, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aap9527