Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557493/ https://www.ncbi.nlm.nih.gov/pubmed/37809094 http://dx.doi.org/10.3389/fimmu.2023.1211505 |
_version_ | 1785117101699104768 |
---|---|
author | Anderson-Crannage, Morgan Ascensión, Alex M. Ibanez-Solé, Olga Zhu, Hongwen Schaefer, Edo Ottomanelli, Darcy Hochberg, Bruno Pan, Jian Luo, Wen Tian, Meijuan Chu, Yaya Cairo, Mitchell S. Izeta, Ander Liao, Yanling |
author_facet | Anderson-Crannage, Morgan Ascensión, Alex M. Ibanez-Solé, Olga Zhu, Hongwen Schaefer, Edo Ottomanelli, Darcy Hochberg, Bruno Pan, Jian Luo, Wen Tian, Meijuan Chu, Yaya Cairo, Mitchell S. Izeta, Ander Liao, Yanling |
author_sort | Anderson-Crannage, Morgan |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-10557493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105574932023-10-07 Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin Anderson-Crannage, Morgan Ascensión, Alex M. Ibanez-Solé, Olga Zhu, Hongwen Schaefer, Edo Ottomanelli, Darcy Hochberg, Bruno Pan, Jian Luo, Wen Tian, Meijuan Chu, Yaya Cairo, Mitchell S. Izeta, Ander Liao, Yanling Front Immunol Immunology 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. Frontiers Media S.A. 2023-09-20 /pmc/articles/PMC10557493/ /pubmed/37809094 http://dx.doi.org/10.3389/fimmu.2023.1211505 Text en Copyright © 2023 Anderson-Crannage, Ascensión, Ibanez-Solé, Zhu, Schaefer, Ottomanelli, Hochberg, Pan, Luo, Tian, Chu, Cairo, Izeta and Liao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Anderson-Crannage, Morgan Ascensión, Alex M. Ibanez-Solé, Olga Zhu, Hongwen Schaefer, Edo Ottomanelli, Darcy Hochberg, Bruno Pan, Jian Luo, Wen Tian, Meijuan Chu, Yaya Cairo, Mitchell S. Izeta, Ander Liao, Yanling Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin |
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 | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557493/ https://www.ncbi.nlm.nih.gov/pubmed/37809094 http://dx.doi.org/10.3389/fimmu.2023.1211505 |
work_keys_str_mv | AT andersoncrannagemorgan inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT ascensionalexm inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT ibanezsoleolga inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT zhuhongwen inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT schaeferedo inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT ottomanellidarcy inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT hochbergbruno inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT panjian inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT luowen inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT tianmeijuan inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT chuyaya inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT cairomitchells inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT izetaander inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin AT liaoyanling inflammationmediatedfibroblastactivationandimmunedysregulationincollagenviideficientskin |