Inflammation-mediated fibroblast activation and immune dysregulation in collagen VII-deficient skin

Frontiers in Immunology

Immunology

Olga Ibanez-Solé¹  Alex M. Ascensión¹  Ander Izeta²  Yaya Chu³  Darcy Ottomanelli³  Wen Luo³  Yanling Liao³  Bruno Hochberg³  Jian Pan³  Meijuan Tian³  Edo Schaefer³  Morgan Anderson-Crannage⁴  Mitchell S. Cairo⁵  Hongwen Zhu⁶ 

[1] Biodonostia Health Research Institute, Tissue Engineering Group, San Sebastian, Spain;Biodonostia Health Research Institute, Tissue Engineering Group, San Sebastian, Spain;Department of Biomedical Engineering and Science, School of Engineering, Tecnun University of Navarra, San Sebastian, Spain;Department of Pediatrics, New York Medical College, Valhalla, NY, United States;Department of Pediatrics, New York Medical College, Valhalla, NY, United States;Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States;Department of Pediatrics, New York Medical College, Valhalla, NY, United States;Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States;Department of Medicine, New York Medical College, Valhalla, NY, United States;Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United States;Department of Research & Development, Guizhou Atlasus Technology Co., Ltd., Guiyang, China;

关键词: epidermolysis bullosa;    inflammation;    immune suppression;    dermal microenvironment;    fibroblast activation;    interleukin-1;    single-cell RNA sequencing;    squamous cell carcinoma;   

DOI  :  10.3389/fimmu.2023.1211505

 received in 2023-04-24, accepted in 2023-08-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Anderson-Crannage, Ascensión, Ibanez-Solé, Zhu, Schaefer, Ottomanelli, Hochberg, Pan, Luo, Tian, Chu, Cairo, Izeta and Liao