Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin
Inflammation is known to play a critical role in all stages of tumorigenesis; however, less is known about how it predisposes the tissue microenvironment preceding tumor formation. Recessive dystrophic epidermolysis bullosa (RDEB), a skin-blistering disease secondary to COL7A1 mutations and associat...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1211505/full |
| _version_ | 1827808849398071296 |
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| author | Morgan Anderson-Crannage Morgan Anderson-Crannage Alex M. Ascensión Olga Ibanez-Solé Hongwen Zhu Edo Schaefer Darcy Ottomanelli Bruno Hochberg Jian Pan Wen Luo Meijuan Tian Yaya Chu Mitchell S. Cairo Mitchell S. Cairo Mitchell S. Cairo Mitchell S. Cairo Ander Izeta Ander Izeta Yanling Liao |
| author_facet | Morgan Anderson-Crannage Morgan Anderson-Crannage Alex M. Ascensión Olga Ibanez-Solé Hongwen Zhu Edo Schaefer Darcy Ottomanelli Bruno Hochberg Jian Pan Wen Luo Meijuan Tian Yaya Chu Mitchell S. Cairo Mitchell S. Cairo Mitchell S. Cairo Mitchell S. Cairo Ander Izeta Ander Izeta Yanling Liao |
| author_sort | Morgan Anderson-Crannage |
| collection | DOAJ |
| description | Inflammation is known to play a critical role in all stages of tumorigenesis; however, less is known about how it predisposes the tissue microenvironment preceding tumor formation. Recessive dystrophic epidermolysis bullosa (RDEB), a skin-blistering disease secondary to COL7A1 mutations and associated with chronic wounding, inflammation, fibrosis, and cutaneous squamous cell carcinoma (cSCC), models this dynamic. Here, we used single-cell RNA sequencing (scRNAseq) to analyze gene expression patterns in skin cells from a mouse model of RDEB. We uncovered a complex landscape within the RDEB dermal microenvironment that exhibited altered metabolism, enhanced angiogenesis, hyperproliferative keratinocytes, infiltration and activation of immune cell populations, and inflammatory fibroblast priming. We demonstrated the presence of activated neutrophil and Langerhans cell subpopulations and elevated expression of PD-1 and PD-L1 in T cells and antigen-presenting cells, respectively. Unsupervised clustering within the fibroblast population further revealed two differentiation pathways in RDEB fibroblasts, one toward myofibroblasts and the other toward a phenotype that shares the characteristics of inflammatory fibroblast subsets in other inflammatory diseases as well as the IL-1-induced inflammatory cancer-associated fibroblasts (iCAFs) reported in various cancer types. Quantitation of inflammatory cytokines indicated dynamic waves of IL-1α, TGF-β1, TNF, IL-6, and IFN-γ concentrations, along with dermal NF-κB activation preceding JAK/STAT signaling. We further demonstrated the divergent and overlapping roles of these cytokines in inducing inflammatory phenotypes in RDEB patients as well as RDEB mouse-derived fibroblasts together with their healthy controls. In summary, our data have suggested a potential role of inflammation, driven by the chronic release of inflammatory cytokines such as IL-1, in creating an immune-suppressed dermal microenvironment that underlies RDEB disease progression. |
| first_indexed | 2024-03-11T22:34:40Z |
| format | Article |
| id | doaj.art-34e1d4686234451eb208aeefa7d3b96f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T22:34:40Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-34e1d4686234451eb208aeefa7d3b96f2023-09-22T19:01:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12115051211505Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skinMorgan Anderson-Crannage0Morgan Anderson-Crannage1Alex M. Ascensión2Olga Ibanez-Solé3Hongwen Zhu4Edo Schaefer5Darcy Ottomanelli6Bruno Hochberg7Jian Pan8Wen Luo9Meijuan Tian10Yaya Chu11Mitchell S. Cairo12Mitchell S. Cairo13Mitchell S. Cairo14Mitchell S. Cairo15Ander Izeta16Ander Izeta17Yanling Liao18Department of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United StatesBiodonostia Health Research Institute, Tissue Engineering Group, San Sebastian, SpainBiodonostia Health Research Institute, Tissue Engineering Group, San Sebastian, SpainDepartment of Research & Development, Guizhou Atlasus Technology Co., Ltd., Guiyang, ChinaDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesDepartment of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United StatesDepartment of Medicine, New York Medical College, Valhalla, NY, United StatesDepartment of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United StatesBiodonostia Health Research Institute, Tissue Engineering Group, San Sebastian, SpainDepartment of Biomedical Engineering and Science, School of Engineering, Tecnun University of Navarra, San Sebastian, SpainDepartment of Pediatrics, New York Medical College, Valhalla, NY, United StatesInflammation is known to play a critical role in all stages of tumorigenesis; however, less is known about how it predisposes the tissue microenvironment preceding tumor formation. Recessive dystrophic epidermolysis bullosa (RDEB), a skin-blistering disease secondary to COL7A1 mutations and associated with chronic wounding, inflammation, fibrosis, and cutaneous squamous cell carcinoma (cSCC), models this dynamic. Here, we used single-cell RNA sequencing (scRNAseq) to analyze gene expression patterns in skin cells from a mouse model of RDEB. We uncovered a complex landscape within the RDEB dermal microenvironment that exhibited altered metabolism, enhanced angiogenesis, hyperproliferative keratinocytes, infiltration and activation of immune cell populations, and inflammatory fibroblast priming. We demonstrated the presence of activated neutrophil and Langerhans cell subpopulations and elevated expression of PD-1 and PD-L1 in T cells and antigen-presenting cells, respectively. Unsupervised clustering within the fibroblast population further revealed two differentiation pathways in RDEB fibroblasts, one toward myofibroblasts and the other toward a phenotype that shares the characteristics of inflammatory fibroblast subsets in other inflammatory diseases as well as the IL-1-induced inflammatory cancer-associated fibroblasts (iCAFs) reported in various cancer types. Quantitation of inflammatory cytokines indicated dynamic waves of IL-1α, TGF-β1, TNF, IL-6, and IFN-γ concentrations, along with dermal NF-κB activation preceding JAK/STAT signaling. We further demonstrated the divergent and overlapping roles of these cytokines in inducing inflammatory phenotypes in RDEB patients as well as RDEB mouse-derived fibroblasts together with their healthy controls. In summary, our data have suggested a potential role of inflammation, driven by the chronic release of inflammatory cytokines such as IL-1, in creating an immune-suppressed dermal microenvironment that underlies RDEB disease progression.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1211505/fullepidermolysis bullosainflammationimmune suppressiondermal microenvironmentfibroblast activationinterleukin-1 |
| spellingShingle | Morgan Anderson-Crannage Morgan Anderson-Crannage Alex M. Ascensión Olga Ibanez-Solé Hongwen Zhu Edo Schaefer Darcy Ottomanelli Bruno Hochberg Jian Pan Wen Luo Meijuan Tian Yaya Chu Mitchell S. Cairo Mitchell S. Cairo Mitchell S. Cairo Mitchell S. Cairo Ander Izeta Ander Izeta Yanling Liao Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin Frontiers in Immunology epidermolysis bullosa inflammation immune suppression dermal microenvironment fibroblast activation interleukin-1 |
| title | Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin |
| title_full | Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin |
| title_fullStr | Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin |
| title_full_unstemmed | Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin |
| title_short | Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin |
| title_sort | inflammation mediated fibroblast activation and immune dysregulation in collagen vii deficient skin |
| topic | epidermolysis bullosa inflammation immune suppression dermal microenvironment fibroblast activation interleukin-1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1211505/full |
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