Expansion of Fcγ Receptor IIIa–Positive Macrophages, Ficolin 1–Positive Monocyte‐Derived Dendritic Cells, and Plasmacytoid Dendritic Cells Associated With Severe Skin Disease in Systemic Sclerosis

Abstract

Objective In this study, 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 from skin biopsy specimens from 12 dcSSc patients and 10 healthy control subjects using single‐cell RNA sequencing. Monocyte‐derived dendritic cells (mo‐DCs) were assessed using immunohistochemical staining and immunofluorescence analyses targeting ficolin‐1 (FCN‐1). Results A t‐distributed stochastic neighbor embedding analysis of single‐cell transcriptome data revealed 12 myeloid cell clusters, 9 of which paralleled previously described healthy control macrophage/DC clusters, and 3 of which were dcSSc‐specific myeloid cell clusters. One SSc‐associated macrophage cluster, highly expressing Fcγ receptor IIIA, was suggested on pseudotime analysis to be derived from normal CCR1+ and MARCO+ macrophages. A second SSc‐associated myeloid population highly expressed monocyte markers FCN‐1, epiregulin, S100A8, and S100A9, but was closely related to type 2 conventional DCs on pseudotime analysis and identified as mo‐DCs. Mo‐DCs were associated with more severe skin disease. Proliferating macrophages and plasmacytoid DCs were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors. Conclusion Transcriptional signatures in these and other myeloid populations indicate innate immune system activation, possibly through Toll‐like receptors and highly up‐regulated chemokines. However, the appearance and activation of myeloid cells varies between patients, indicating potential differences in the underlying pathogenesis and/or temporal disease activity in dcSSc.

Large-scale analysis of longitudinal skin gene expression in systemic sclerosis reveals relationships of immune cell and fibroblast activity with skin thickness and a trend towards normalisation over time

“…As with all gene expression studies examining bulk tissue samples, conclusions about cell type-specific gene expression profiles are based on inferences from prior gene expression datasets. Single cell analyses are beginning to provide a more granular understanding of the cellular composition and cell-specific gene expression profiles in SSc skin 26–28. The relatively low prevalence of anti-centromere antibody in this study may reflect a referral bias, in which SSc patients with severe skin or internal organ involvement are more likely to be referred to our scleroderma specialty clinic than centromere positive patients; this might affect the generalisability of our results.…”

A map of the spatial distribution and tumour‐associated macrophage states in glioblastoma and grade 4 IDH‐mutant astrocytoma

“…Given that tumour-infiltrating myeloid cells are a heterogeneous population with different ontogenies and activation states, we performed unbiased clustering of 11,897 myeloid cells in GBM. A monocyte cluster (with marker genes FCN1, VCAN, and LYZ) [7,12], six TAM clusters derived either from peripheral monocytes (Mo-TAM, with marker genes EMILIN2 and LGALS3) or from brain-resident microglia (Mg-TAMs, with marker genes TMEM119, P2RY12, and SALL1) [13][14][15], a dendritic cell cluster (CD1C, FCER1A, and CLEC10A), and a proliferative myeloid cluster (Myeloid_pro., MKI67, TOP2A, and PCNA) were identified based on the expression of cell-type signature genes (Figure 1C,D and supplementary material, Table S3). The prevalence of the abovementioned myeloid clusters was confirmed across primary and recurrent GBM specimens (n = 11) using scRNA-seq data deposited in the Gene Expression Omnibus (GEO) database (GSE163120, supplementary material, Figure S3) [7].…”

Revisiting the disease specificity and nomenclature of ficolin‐1–positive monocyte‐derived dendritic cells in diffuse cutaneous systemic sclerosis: comment on the article by Xue et al

“…We thank Dr. Sarfati and colleagues for their thoughtful comments on our recent description of myeloid cell phenotypes in dcSSc skin. Our previous biomarker articles, in which we reported strong correlations between macrophage gene expression and presentation of systemic sclerosis clinical disease in skin and lung (1,2), led us to better understand the specific myeloid population(s) potentially driving disease. In our single-cell RNA-sequencing study discussed by Sarfati et al, we highlighted not only the increase in certain myeloid populations in dcSSc skin but also reemphasized the tremendous heterogeneity of intensity of inflammatory infiltrates in dcSSc skin.…”