Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation
Allison C. Billi, Feiyang Ma, Olesya Plazyo, Mehrnaz Gharaee‐Kermani, Rachael Wasikowski, Grace A. Hile, Xianying Xing, Christine M. Yee, Syed Rizvi, Mitra P. Maz, Céline C. Berthier, Fei Wen, Lam C. Tsoi, Matteo Pellegrini, Robert L. Modlin, Jóhann E. Guðjónsson, J. Michelle Kahlenberg
Abstract
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.