Background/Purpose: Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus (LE) and other autoimmune conditions. Photosensitive lesions can be disfiguring and photosensitivity can be associated with flares of systemic disease. Increased UVR-induced keratinocyte apoptosis is thought to play a role in the pathogenesis, but factors that regulate keratinocyte apoptosis in photosensitivity are poorly understood. Langerhans cells (LCs), mononuclear phagocytes positioned primarily in the epidermis, can have regulatory roles. As LCs are closely associated with keratinocytes, we hypothesized that LCs can limit UVR-induced keratinocyte apoptosis and skin injury.

Methods: We exposed mice to UVR at a minimal erythema dosage and 24 hours and 5 days later, harvested ear skin for immunohistochemistry to measure activated caspase 3, for flow cytometry to enumerate monocyte infiltration, for histology to measure epidermal thickness, and for toluidine blue dye assays to measure epidermal permeability. Primary mouse and human keratinocyte cultures were exposed to UVR in the presence or absence of LCs and keratinocyte apoptosis was measured. Skin sections from healthy controls and SLE patients were stained for immunofluorescence analysis of LC numbers and epidermal markers.

Results: Here, 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 absence of LCs in Langerin-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 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 LE (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and topical EGFR ligand reduces photosensitivity.

Conclusion: 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 LE and potentially other autoimmune conditions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-protective-langerhans-cell-keratinocyte-axis-that-is-dysfunctional-in-photosensitivity/