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

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.

Brief communication: Long-term absence of Langerhans cells alters the gene expression profile of keratinocytes and dendritic epidermal T cells

“…The commonly upregulated pathways included different forms of cell adhesions (focal, adherent and tight)-, ribosome and RNA biogenesis-, autophagy-, bacterial invasion/infection-, MAPK-and ErbB signaling pathways (Fig 2D). Alterations in adhesion molecules and the ErbB signaling pathway in KCs, in the absence of LCs, were recently reported [24,33]. The downregulated pathways showed considerably less overlap between these two cell types and included some of the amino acid degradation pathways ( Fig 2D).…”

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent

“…Here, we observed that both local and systemic early production of IFN-I following skin exposure to UVB was almost entirely cGAS dependent. In normal situations, acute inflammation is resolved through many reparative mechanisms that involve T-regulatory cells, Langerhans cells, and anti-inflammatory cytokines such as IL-10 (Shipman et al, 2018;Wolf et al, 2019;Yamazaki et al, 2018). Why SLE patients fail to control the inflammatory response in the skin and elsewhere is a critical question that will benefit from understanding the pathogenetic pathways involved.…”

Brief communication: Long-term absence of Langerhans cells alters the gene expression profile of keratinocytes and dendritic epidermal T cells

“…The commonly upregulated pathways included different forms of cell adhesions (focal, adherent and tight)-, ribosome and RNA biogenesis-, autophagy-, bacterial invasion/infection-, MAPK- and ErbB signaling pathways ( Figure 2d ). Alterations in adhesion molecules and the ErbB signaling pathway in KCs, in the absence of LCs, were recently reported(22,31). The downregulated pathways showed considerably less overlap between these two cell types and included some of the amino acid degradation pathways ( Figure 2d ).…”