Non-lesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation

• Published in: Science translational medicine 2022-04, Vol.14 (642), p.eabn2263-eabn2263
• Main Authors: Billi, Allison C., Ma, Feiyang, Plazyo, Olesya, Gharaee-Kermani, Mehrnaz, Wasikowski, Rachael, Hile, Grace A., Xing, Xianying, Yee, Christine M., Rizvi, Syed M., Maz, Mitra P., Berthier, Celine C., Wen, Fei, Tsoi, Lam C., Pellegrini, Matteo, Modlin, Robert L., Gudjonsson, Johann E., Kahlenberg, J. Michelle
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.abn2263

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Previous studies suggest that non-lesional 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 lupus patients represents a type I interferon-rich, prelesional environment that skews gene transcription in all major skin cell types and dramatically distorts predicted cell-cell communication networks. We also show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining pro-inflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and non-lesional skin in lupus and suggest a role for skin education of CD16+ dendritic cells in CLE pathogenesis. Non-lesional and lesional lupus skin share inflammatory phenotypes that drive activation of CD16+ dendritic cells. Comprehending Cutaneous Lupus Cutaneous lupus erythematosus (CLE) is disfiguring skin condition that affects most patients with systemic lupus erythematosus (SLE) and can be resistant to treatment even when systemic disease is responsive. Billi et al. analyzed analyzed CLE lesions and paired normal-appearing skin biopsies, as well as circulating immune cell subsets, to better understand changes in the skin that drive CLE pathogenesis. Using single-cell RNA sequencing and spatial RNA sequencing, they identified a type I IFN-rich signature in prelesional, normal looking skin that influenced transcription and cell-cell communication for all major skin cell types. CD16+ dendritic cells, which are associated with SLE, were also shaped by the type I IFN environment, and cells in these sites shifted toward a pro-inflammatory phenotype. Together these data provide insights into transcriptional changes in the skin that contribute to CLE pathogenesis.