Integrated bulk and single-cell RNA-sequencing identified disease-relevant monocytes and a gene network module underlying systemic sclerosis

Kobayashi, Satomi; Nagafuchi, Yasuo; Okubo, Masaaki; Sugimori, Yusuke; Shirai, Hiroko; Hatano, Hiroaki; Maeda, Joji; Yanaoka, Haruyuki; Takeshima, Yusuke; M, Ota; Iwasaki, Yukiko; Sumitomo, Shuji; Okamura, Tomohisa; Yamamoto, Kazuhiko; Shoda, Hirofumi; Fujio, Keishi

doi:10.1016/j.jaut.2020.102547

Cited by 27 publications

(23 citation statements)

References 47 publications

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“…The results of scRNA-seq showed that there were six DC subpopulations in skin biopsies of the HC, including cDC1 (CLEC9A + DCs), two subsets of cDC2 (CXorf21 + DCs and MCOLN2 + DCs), a novel DC subtype (LAMP3 + DCs), a cluster of proliferating DCs (KIAA0101 + DCs), and a Langerhans cell subset (Langerin + DCs). FCN1 + , the monocyte-derived DC marker, was related to cDC2 in the pseudo-time distribution and existed solely in dcSSc, which was associated with severe skin fibrosis and had been mentioned in previous studies (Kobayashi et al, 2021). In addition, pDCs derived from the lymphoid progenitor cells also appeared almost exclusively in the skin in dcSSc (Xue et al, 2020;Xue et al, 2021).…”

Section: Dendritic Cellsmentioning

confidence: 55%

“…ScRNA-seq was further used to explore the details of monocytes, and seven subsets (PM0-PM6) were finally identified. The PM0 cluster typically expressed the abovementioned inflammatory co-expression genes and had similar transcriptomics with IL1B + FCN1 hi monocytes in the lung tissue of SSc-associated interstitial lung disease (SSc-ILD) (Kobayashi et al, 2021) (Table 1). According to previous studies, IL1B could be a key pro-fibrotic mediator (Park et al, 2018), and IL1B + FCN1 hi cells were involved in skin and lung fibrosis, indicating that the cluster might be a new therapeutic target for SSc (Aran et al, 2019).…”

Section: Monocytesmentioning

confidence: 96%

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Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

et al. 2022

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Systemic sclerosis (SSc) is a multisystem rheumatic disease characterized by vascular dysfunction, autoimmune abnormalities, and progressive organ fibrosis. A series of studies in SSc patients and fibrotic models suggest that immune cells, fibroblasts, and endothelial cells participate in inflammation and aberrant tissue repair. Furthermore, the growing number of studies on single-cell RNA sequencing (scRNA-seq) technology in SSc elaborate on the transcriptomics and heterogeneities of these cell subsets significantly. In this review, we summarize the current knowledge regarding immune cells and stromal cells in SSc patients and discuss their potential roles in SSc pathogenesis, focusing on recent advances in the new subtypes by scRNA-seq.

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Section: Dendritic Cellsmentioning

confidence: 55%

Section: Monocytesmentioning

confidence: 96%

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

et al. 2022

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“…Moreover, a change in skin severity score that includes a 415 gene signature has been shown to correlate with mRSS (84), although to date no studies have corroborated the skin severity score. Recently, a few groups examined gene expression specifically in individual immune populations such as monocytes or macrophages using bulk or single cell RNA-seq (56, 85, 86). While these studies support the role for the type I interferon as well as the IL-1β pathway in bulk SSc monocytes (CM and NCM), neither study examined any clinical associations (56, 85).…”

Section: Discussionmentioning

confidence: 99%

Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in SSc Patients

Makinde

Dunn

Gadhvi

et al. 2022

Preprint

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Background/Purpose: Patients with systemic sclerosis (SSc) display a complex clinical phenotype. There are numerous studies that relate transcriptional signatures from PBMC or whole skin of SSc patients to disease activity. However, analyses of whole tissue RNA-sequencing studies are subjected to changes in cellular composition that can drive gene expression signatures and a loss of the ability to detect biologically important transcriptional changes within minority cell populations. Here, we focused on circulating monocytes, which have been shown to exist as two central populations classical (CM) and non-classical (NCM). Methods: SSc patients were recruited from four different sites that form PRESS: Northwestern University, University of Texas, University of Michigan and University of Utah. Comprehensive clinical data were collected for all patients. We isolated CM and NCM monocytes from these patients and age, sex, and race-matched healthy volunteers were used as controls. RNA-seq was performed on CM and NCM populations as well as on isolated bulk macrophages from skin. Results: We first performed RNA-seq on CM, which are the predominant population in circulation. In order to capture the variability across the SSc cohort, we defined 1790 differentially expressed genes in each patient. We then used these genes to cluster patients into 3 subgroups: Groups A-C. Group A exhibited the strongest interferon signature and innate immune pathways. Group B patients expressed genes in the same pathways but was also enriched for response to cAMP and corticosteroids. Both Group B and Group C exhibited upregulation of genes associated with vasculature development and blood vessel formation. Group C uniquely upregulated TGFB pathways. Next, we performed RNA-seq on NCM isolated from the same patients. When NCM were clustered based on the same 1790 genes as CM, we found that Groups A and C were recapitulated, while Group B was less cohesive. Our analysis stratified SSc patients based on their transcriptional profiles in monocytes but was agnostic to their clinical presentation. We found that Group B and C patients exhibited significantly worsened lung function at the time of monocyte isolation than Group A patients. However, there were no significant differences in skin disease. We then isolated macrophages from skin biopsies of SSc patients and showed that the transcriptional profile of Group A and C in SSc patients was conserved. We also used gene expression data from another study on monocytes which stratified patients based on disease presentation. We found that Group A accurately distinguished dcSSc and ncSSc patients from controls, but not lcSSc. Conclusion: We are the first to show that transcriptomic analysis of classical and non-classical circulating monocytes can unbiasedly stratify SSc patients and correlate with disease activity outcome measures.

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“…In the current study, PLAUR had interactions with multiple candidate key genes and was found to participate in complement and coagulation cascades, neutrophil-associated immune response, and coagulation-related biological responses. Although the exact function of DM-ILD remains unclear, PLAUR has been shown to be associated with autoimmune disease ( Göbel et al, 2016 ; Kobayashi et al, 2021 ) and relates to pulmonary dysfunction. Thus, PLAUR may be involved in the pathogenesis of DM-ILD through immune-mediated mechanism.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Sequencing Identifies PLAUR as an Important Player in Patients With Dermatomyositis-Associated Interstitial Lung Disease

et al. 2021

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Dermatomyositis (DM), an inflammatory disorder, is often associated with interstitial lung disease (ILD). However, the underlying mechanism remains unclear. Our study performed RNA sequencing (RNA-seq) and integrative bioinformatics analysis of differentially expressed genes (DEGs) in patients with dermatomyositis-associated interstitial lung disease (DM-ILD) and healthy controls. A total of 2,018 DEGs were identified between DM-ILD and healthy blood samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that DEGs were mainly involved in immune- and inflammatory-related biological processes and pathways. Disease ontology (DO) enrichment analysis identified 35 candidate key genes involved in both skin and lung diseases. Meanwhile, a total of 886 differentially expressed alternative splicing (AS) events were found between DM-ILD and healthy blood samples. After overlapping DEGs with differential AS genes, the plasminogen activator and urokinase receptor (PLAUR) involved in immune-related biological processes and complement and coagulation cascades was screened and identified as the most important gene associated with DM-ILD. The protein–protein interaction (PPI) network revealed that PLAUR had interactions with multiple candidate key genes. Moreover, we observed that there were significantly more neutrophils and less naive B cells in DM-ILD samples than in healthy samples. And the expression of PLAUR was significantly positively correlated with the abundance of neutrophils. Significant higher abundance of PLAUR in DM-ILD patients than healthy controls was validated by RT-qPCR. In conclusion, we identified PLAUR as an important player in regulating DM-ILD by neutrophil-associated immune response. These findings enrich our understanding, which may benefit DM-ILD patients.

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Integrated bulk and single-cell RNA-sequencing identified disease-relevant monocytes and a gene network module underlying systemic sclerosis

Cited by 27 publications

References 47 publications

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in SSc Patients

Transcriptome Sequencing Identifies PLAUR as an Important Player in Patients With Dermatomyositis-Associated Interstitial Lung Disease

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