Early Life Inflammation Primes a Th2-Fibroblast Niche in Skin
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ABSTRACT:
PROVIDER: PRJNA758894 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15668550.fastq.gz | Fastqsanger.gz | |||
| SRR15668551.fastq.gz | Fastqsanger.gz | |||
| SRR15668552.fastq.gz | Fastqsanger.gz | |||
| SRR15668553.fastq.gz | Fastqsanger.gz | |||
| SRR15668554.fastq.gz | Fastqsanger.gz |
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Project description:Inflammation early in life can prime the local immune milieu of peripheral tissues, causing lasting changes in immunologic tone that confer disease protection or susceptibility. The cellular and molecular mechanisms that incite changes in immune tone in many nonlymphoid tissues remain largely unknown. We find that time-limited neonatal inflammation induced by transient reduction of neonatal regulatory T cells (Tregs) causes a dramatic dysregulation of subcutaneous tissue in murine skin, accompanied by the selective accumulation of Th2 cells within a distinct microanatomic niche. Th2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as Th2-interacting fascial fibroblasts (TIFFs), which expand in response to Th2 cytokines to form subcutaneous fibrous bands. Activation of the Th2-TIFF niche by neonatal inflammation primes skin for altered reparative responses to wounding. We further identify fibroblasts in healthy human skin expressing the TIFF transcriptional signature and find these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a novel Th2 niche in skin, functionally characterize a disease-associated fibroblast population, and suggest a mechanism of immunologic priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells, establishing an immunological set-point in tissues that is maintained throughout life.
2021-10-01 | GSE183031 | GEO
Project description:Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2-TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life.
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Project description:Fibroblasts residing in the connective tissue of all organs constitute the stem cell niche particularly in connective tissue rich organs like skin. Though the impact of the connective tissue resident fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. Here, we report a novel mechanism of redox-dependent activation of the transcription factor JunB, which through concomitant upregulation of cyclin dependent kinase inhibitor p16INK4A and repression of IGF-1 dependent cell growth and protein translation initiates the installment of irreversible fibroblast senescence. Fibroblast senescence in turn profoundly disrupts the metabolic and structural niche and its essential interactions with different stem cells thus enforcing depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast niche-specific knock out mouse - by the reinstatement of IGF-1 and p16 levels - fully restored skin stem cell pools and overall tissue integrity of the skin. We here uncovered a previously unreported role of JunB in the control of the endogenous connective tissue niche and identified promising targets to combat skin aging and associated pathologies.
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Project description:Bioactive sphingolipids serve as an essential building block of membranes, forming a selective barrier ensuring subcellular compartmentalization and facilitating cell type-specific intercellular communication through regulation of the plasma membrane receptor repertoire. How the cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem-cell specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in the skin epidermis. Deletion of CerS4 in the epidermis prevents the effective establishment of the adult hair follicle bulge stem cell (HFSCs) niche due to altered differentiation trajectories of HFSC precursors towards upper hair follicle and inner bulge fates. Mechanistically, the HFSC differentiation defects arise from a stem cell intrinsic imbalance of key ceramides and sphingolipids, and associated hyperactivity of canonical Wnt signaling. The lack of HFSCs leads to disruption of hair follicle architecture and hair follicle barrier function, ultimately triggering a Th2-dominated immune infiltration closely resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in epidermal stem cell homeostasis and the role of an intact stem cell niche in maintaining an intact skin barrier.
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Project description:To investigate the regulation of pathogenic Th2 (pTh2) cells and the role of histone deacetylase 1 (HDAC1) in the respective processes, we used a new in vitro protocol for generating pTh2 cells and performed qunatitative mass spectrometry analysis based on TMTpro 16plex multiplexing to analyze proteomes. We profiled classical Th2 and pTh2 cells from wild type (WT) mice and mice with a T cell-specific deletion of HDAC1 (HDAC1-cKO).
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Project description:Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumour progression. Myofibroblasts have previously mostly been distinguished from normal fibroblasts only by the expression of α smooth muscle actin (αSMA). We now identify AOC3, a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast reacting monoclonal antibody (mAb), PR2D3. The normal and tumour tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by non-enzymatic procedures. Whole genome microarray mRNA expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly expressed differentially between these two cell types; NKX2-3 and LRRC17 are expressed in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. Transforming Growth Factor β (TGFβ) substantially down-regulated AOC3 expression in myofibroblasts but not in skin fibroblasts, in which it dramatically increased the expression of αSMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and an increased expression of the fibroblast associated gene, SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3 and other markers, are a distinctly different cell type from TGFβ activated fibroblasts. colorectal myofibroblast specific markers and expression profiles were sought by comparing four primary myofibroblast cultures to a panel of four dermal and foreskin fibroblast cell lines
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