Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation.

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Previous studies suggest that nonlesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA sequencing and spatial RNA sequencing. We demonstrate that normal-appearing skin of patients with lupus represents a type I interferon-rich, prelesional environment that skews gene transcription in all major skin cell types and markedly distorts predicted cell-cell communication networks. We also show that lupus-enriched CD16 ⁺ dendritic cells undergo robust interferon education in the skin, thereby gaining proinflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and nonlesional skin in lupus and suggest a role for skin education of CD16 ⁺ dendritic cells in CLE pathogenesis.