Dataset Information

Dendritic cells drive profibrotic inflammation and aberrant T cell polarization in systemic sclerosis.

ABSTRACT:

Objectives

SSc is a devastating autoimmune disease characterized by fibrosis and obliterative vasculopathy affecting the skin and visceral organs. While the processes mediating excessive extracellular matrix deposition and fibroblast proliferation are clear, the exact link between autoimmunity and fibrosis remains elusive. Th17 cells have been proposed as critical drivers of profibrotic inflammation during SSc, but little is known about the immune components supporting their pathogenic role. Our aim was to determine cytokine responses of stimulated monocyte-derived dendritic cells (Mo-DCs) and to determine how they influence T-cell cytokine production in SSc.

Material and methods

Dendritic cells (DCs) activate and shape T cell differentiation by producing polarizing cytokines. Hence, we investigated the cytokine responses of monocyte-derived DCs (Mo-DCs) from patients with limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc) and healthy controls (HCs) after stimulation with toll-like receptor (TLR) agonists. Also, using co-culture assays, we analysed T cell subpopulations after contact with autologous TLR-activated Mo-DCs.

Results

In general, we observed an increased production of Th17-related cytokines like IL-1β, IL-17F, IL-21 and IL-22 by SSc compared with HC Mo-DCs, with variations between lcSSc vs dcSSc and early- vs late-stage subgroups. Noticeably, we found a significant increment in IL-33 production by Mo-DCs in all SSc cases regardless of their clinical phenotype. Strikingly, T cells displayed Th2, Th17 and dual Th2-Th17 phenotypes after exposure to autologous TLR-stimulated Mo-DCs from SSc patients but not HCs. These changes were pronounced in individuals with early-stage dcSSc and less significant in the late-stage lcSSc subgroup.

Conclusions

Our findings suggest that functional alterations of DCs promote immune mechanisms favouring the aberrant T cell polarization and profibrotic inflammation behind clinical SSc heterogeneity.

SUBMITTER: Choreno-Parra JA

PROVIDER: S-EPMC10070068 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Dendritic cells drive profibrotic inflammation and aberrant T cell polarization in systemic sclerosis.

Choreño-Parra José Alberto JA Cervantes-Rosete Diana D Jiménez-Álvarez Luis Armando LA Ramírez-Martínez Gustavo G Márquez-García José Eduardo JE Cruz-Lagunas Alfredo A Magaña-Sánchez Ana Yelli AY Lima Guadalupe G López-Maldonado Humberto H Gaytán-Guzmán Emanuel E Caballero Adrian A Fernández-Plata Rosario R Furuzawa-Carballeda Janette J Mendoza-Milla Criselda C Navarro-González Maria Del Carmen MDC Llorente Luis L Zúñiga Joaquín J Rodríguez-Reyna Tatiana Sofía TS

Rheumatology (Oxford, England) 20230401 4

<h4>Objectives</h4>SSc is a devastating autoimmune disease characterized by fibrosis and obliterative vasculopathy affecting the skin and visceral organs. While the processes mediating excessive extracellular matrix deposition and fibroblast proliferation are clear, the exact link between autoimmunity and fibrosis remains elusive. Th17 cells have been proposed as critical drivers of profibrotic inflammation during SSc, but little is known about the immune components supporting their pathogenic r ...[more]

PMID: 36063053

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Project description:ObjectiveSystemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with SSc with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic secreted phosphoprotein 1 (SPP1)-expressing macrophages in SSc-ILD. This study was undertaken to define the transcriptome and chromatin structural changes of SPP1 SSc-ILD macrophages in order to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype.MethodsWe performed single-cell RNA sequencing (scRNA-Seq) on 11 explanted SSc-ILD and healthy control lung samples, as well as single-cell assay for transposase-accessible chromatin sequencing on 5 lung samples to define altered chromatin accessibility of SPP1 macrophages. We predicted transcription factors regulating SPP1 macrophages using single-cell regulatory network inference and clustering (SCENIC) and determined transcription factor binding sites associated with global alterations in SPP1 chromatin accessibility using Signac/Seurat.ResultsWe identified distinct macrophage subpopulations using scRNA-Seq analysis in healthy and SSc-ILD lungs and assessed gene expression changes during the change of healthy control macrophages into SPP1 macrophages. Analysis of open chromatin validated SCENIC predictions, indicating that microphthalmia-associated transcription factor, transcription factor EB, activating transcription factor 6, sterol regulatory element binding transcription factor 1, basic helix-loop-helix family member E40, Kruppel-like factor 6, ETS variant transcription factor 5, and/or members of the activator protein 1 family of transcription factors regulate SPP1 macrophage differentiation.ConclusionOur findings shed light on the underlying changes in chromatin structure and transcription factor regulation of profibrotic SPP1 macrophages in SSc-ILD. Similar alterations in SPP1 macrophages may underpin fibrosis in other organs involved in SSc and point to novel targets for the treatment of SSc-ILD, specifically targeting profibrotic macrophages.

Dataset Information

Dendritic cells drive profibrotic inflammation and aberrant T cell polarization in systemic sclerosis.

Objectives

Material and methods

Results

Conclusions

Publications

Dendritic cells drive profibrotic inflammation and aberrant T cell polarization in systemic sclerosis.

Similar Datasets

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