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IL-17 activates dermal reticular fibroblasts to promote neutrophil recruitment and host defense [scRNAseq]

ABSTRACT: The complex system by which the skin regulates immune responses to the external environment is unclear. Here, we investigated cell-cell interactions underlying cutaneous defense against S. aureus. Single-cell transcriptomics (scRNA-Seq) and unbiased network analysis revealed unexpected, dominant IL-17-mediated dermal reticular fibroblast-to-neutrophil communication. Multi-faceted in vitro omics studies demonstrated that IL-17 synergized with several factors including TNF⍺ to induce fibroblast NFKBIZ and chemokine secretion. Cultured fibroblasts drove robust neutrophil recruitment through NFKBIZ-dependent CXCR2 and CXCR4 ligands. Mice lacking IL-17R in fibroblasts (PdgfraΔIl17ra) were generated to determine the significance of fibroblast-neutrophil communication. PdgfraΔIl17ra mice exhibited drastically reduced skin neutrophilia in multiple disease models and reduced defense against S. aureus. These findings were translated to humans by comprehensive analysis of biopsies from psoriasis patients on and off anti-IL-17 treatment. Thus, dermal fibroblasts are critical for skin type 17 inflammation and represent a novel target for treatment of infection and inflammatory disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE230512 | GEO | 2024/02/15

REPOSITORIES: GEO

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IL-17 activates dermal reticular fibroblasts to promote neutrophil recruitment and host defense [RNAseq]

Project description:The complex system by which the skin regulates immune responses to the external environment is unclear. Here, we investigated cell-cell interactions underlying cutaneous defense against S. aureus. Single-cell transcriptomics (scRNA-Seq) and unbiased network analysis revealed unexpected, dominant IL-17-mediated dermal reticular fibroblast-to-neutrophil communication. Multi-faceted in vitro omics studies demonstrated that IL-17 synergized with several factors including TNF⍺ to induce fibroblast NFKBIZ and chemokine secretion. Cultured fibroblasts drove robust neutrophil recruitment through NFKBIZ-dependent CXCR2 and CXCR4 ligands. Mice lacking IL-17R in fibroblasts (PdgfraΔIl17ra) were generated to determine the significance of fibroblast-neutrophil communication. PdgfraΔIl17ra mice exhibited drastically reduced skin neutrophilia in multiple disease models and reduced defense against S. aureus. These findings were translated to humans by comprehensive analysis of biopsies from psoriasis patients on and off anti-IL-17 treatment. Thus, dermal fibroblasts are critical for skin type 17 inflammation and represent a novel target for treatment of infection and inflammatory disease.

2024-02-14 | GSE230511 | GEO

Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice

Project description:Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils. Lesional skin biopsies obtained from C57BL/6J WT mice or IL-1R-deficient mice at 4 hours post-infection with Staphylococcus aureus. Uninfected skin biopsies were also collected from WT and IL-1R-deficient mice.

2012-12-05 | E-GEOD-36826 | biostudies-arrayexpress

Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice

2012-12-05 | GSE36826 | GEO

Single-cell transcriptomes of the aging human skin reveal loss of fibroblast priming

Project description:Fibroblasts are the main dermal cell type and are essential for the architecture and function of human skin. Important differences have been described between fibroblasts localized in distinct dermal layers, and these cells are also known to perform varied functions. However, this phenomenon has not been analyzed comprehensively yet. Here we have used single-cell RNA sequencing to analyze >15,000 cells from a sun-protected area in young and old donors. Our results define four main fibroblast subpopulations that can be spatially localized and functionally distinguished. Importantly, intrinsic aging reduces this fibroblast ‘priming’, generates distinct expression patterns of skin aging-associated genes, and substantially reduces the interactions of dermal fibroblasts with other skin cell types. Our work thus provides comprehensive evidence for a functional specialization of human dermal fibroblasts and suggests that the age-related loss of fibroblast priming contributes to human skin aging.

2020-03-31 | GSE130973 | GEO

Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapy

Project description:To investigate the contribution of fibroblast-derived extracellular matrices (ECMs) to the resistance to targeted therapies in BRAF-mutated melanoma cells, we generated native-like 3D ECMs from human primary fibroblasts obtained from healthy individuals or melanoma patients. Cell-derived matrices from human dermal fibroblasts (HDF), skin melanoma associated fibroblasts (MAF) and two different lymph node fibroblast reticular cells (FRC) were denuded of cells and their composition was analyzed by mass spectrometry.

2021-11-12 | PXD026645 | Pride

Effect of IL-1b on primary human skin-relevant cells

Project description:Analyses of IL-1b-induced transcriptome in various skin-relevant cell types (keratinocytes, dermal fibroblasts, dermal microvascular endothelial cells, mononuclear immune cells) by RNASeq method disclosed an overlap of upregulated molecules among the different cell types. Matching cellular IL-1 receptor levels, dermal fibroblasts showed both the strongest and broadest IL-1b response.

2020-11-03 | GSE120784 | GEO

EphB2 receptor promotes dermal fibrosis in systemic sclerosis

Project description:Objectives: Eph/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc). Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from SSc patients and healthy controls, which was followed by in vivo analysis of fibroblast-specific EphB2 deficient mice. Results: Expression of EphB2 is upregulated in SSc skin tissue and explanted SSc dermal fibroblasts compared to healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-β (TGFβ) cytokines upregulate EphB2 in dermal fibroblasts via non-canonical TGFβ/SMAD signaling and silencing EphB2 in dermal fibroblasts is sufficient to dampen TGFβ-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge. Conclusion: Our data implicate EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.

2024-04-10 | GSE253089 | GEO

Single Cell and Spatial Sequencing Define Processes by which Keratinocytes and Fibroblasts Amplify Inflammatory Responses in Psoriasis

Project description:The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occurred within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2+ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2+ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2+ myeloid cells, CCR7+ LAMP3+ dendritic cells, and CXCR4 expressed on both CD8+ Tc17 cells and keratinocytes, respectively. The SFRP2+ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an unprecedented view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.

2023-05-07 | GSE225475 | GEO

The expression profiles of extracellular matrix-related genes in the presence or absence of IL-17A or -17F as measured with the PCR array in systemic sclerosis (SSc) dermal fibroblasts

Project description:We examined the effect of IL-17 signaling pathway on extracellular matrix (ECM) expression and the involvement of IL-17 signaling pathway in pathogenesis of SSc. To identify differences in the expression pattern of ECM genes in IL-17A- or IL-17F-treated cells, we performed PCR array analysis, consisting of 84 ECM-related genes. Normal human dermal fibroblasts were cultured until they were confluent, and then stimulated with IL-17A or IL-17F for 12 hours, and total RNA was extracted. A mixture of equal amounts of mRNAs from three normal fibroblasts was prepared in the presence or absence of IL-17A or -17F, and mRNA expression profile was evaluated using PCR Array. Normal fibroblasts were obtained by skin biopsies from 3 healthy donors. Fibroblasts from donors were used and treated separately as indicated in the summary. Equal amount total RNA from each donor was pooled prior to gene expression analysis.

2012-01-01 | E-GEOD-33581 | biostudies-arrayexpress

Spatial and single-cell transcriptional profiling identifies functionally distinct human dermal fibroblast subpopulations

Project description:Fibroblasts synthesize the extracellular matrix of connective tissue and play an essential role in maintaining tissue integrity. We have previously shown that mouse skin connective tissue, the dermis, is comprised of functionally distinct fibroblast lineages. However, the extent of fibroblast heterogeneity in human skin is unknown. Here, using a combination of spatial transcriptional profiling of human and mouse dermis and single cell transcriptional profiling of human dermal fibroblasts, we show that there are at least four distinct fibroblast populations in adult human skin. We define markers permitting prospective isolation of these cells and show that although marker expression is rapidly lost in culture, different fibroblast subpopulations retain distinct functionality in terms of Wnt signalling, T cell communication and the ability to support human epidermal reconstitution in organotypic culture. Furthermore, while some fibroblast subpopulations are spatially segregated, others are not. These findings have profound implications for normal wound healing and diseases characterized by excessive fibrosis, and suggest that ex vivo expansion or in vivo ablation of specific fibroblast subpopulations may have therapeutic applications.

2018-02-12 | GSE109822 | GEO

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