Expansion of FCGR3A+ macrophages, FCN1+ mo-DC, and plasmacytoid dendritic cells associated with severe skin disease in systemic sclerosis.

Objective We sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin. Methods We analyzed the transcriptomes of 2,465 myeloid cells skin biopsies from 10 healthy controls (HCs) and 12 dcSSc patients by single-cell RNA-sequencing (scRNA-seq). Monocyte-derived dendritic cells were stained by immunohistochemistry and immunofluorescence targeting FCN1. Results T-stochastic neighbor embedding analysis of single cell transcriptome data revealed 12 myeloid cell clusters, nine of which paralleled previously described HC Mφ/DC clusters and three of which were dcSSc-specific myeloid cell clusters. One SSc-associated macrophage cluster, highly expressing FCGR3A, on pseudotime analysis was suggested to derive from normal CCR1+ and MARCO+ macrophages. A second SSc-associated myeloid population, highly expressed monocyte markers: FCN1, EREG, S100A8 and S100A9, but was closely related to cDC2 on pseudotime analysis and identified as Mo-DC. Mo-DC were associated with more severe skin disease. Proliferating macrophages and plasmacytoid dendritic cells were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors. Conclusions Transcriptional signatures in these and other myeloid populations indicate innate immune activation, possibly through TLRs, and highly upregulated chemokines. However, the appearance and activation of myeloid cells is variable between patients, indicating differing underlying pathogenesis and/or temporal disease activity.