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IL-6 trans-signaling in a humanized mouse model of scleroderma

Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop...

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Autores principales: Odell, Ian D., Agrawal, Kriti, Sefik, Esen, Odell, Anahi V., Caves, Elizabeth, Kirkiles-Smith, Nancy C., Horsley, Valerie, Hinchcliff, Monique, Pober, Jordan S., Kluger, Yuval, Flavell, Richard A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500188/
https://www.ncbi.nlm.nih.gov/pubmed/37669366
http://dx.doi.org/10.1073/pnas.2306965120
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author Odell, Ian D.
Agrawal, Kriti
Sefik, Esen
Odell, Anahi V.
Caves, Elizabeth
Kirkiles-Smith, Nancy C.
Horsley, Valerie
Hinchcliff, Monique
Pober, Jordan S.
Kluger, Yuval
Flavell, Richard A.
author_facet Odell, Ian D.
Agrawal, Kriti
Sefik, Esen
Odell, Anahi V.
Caves, Elizabeth
Kirkiles-Smith, Nancy C.
Horsley, Valerie
Hinchcliff, Monique
Pober, Jordan S.
Kluger, Yuval
Flavell, Richard A.
author_sort Odell, Ian D.
collection PubMed
description Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC. We identified that scleroderma skin grafts contained both skin and bone marrow–derived human CD4 and CD8 T cells along with human endothelial cells and pericytes. Unlike healthy skin, fibroblasts in scleroderma skin were depleted and replaced by mouse fibroblasts. Furthermore, HSC engraftment alleviated multiple signatures of fibrosis, including expression of collagen and interferon genes, and proliferation and activation of human T cells. Fibrosis improvement correlated with reduced markers of T cell activation and expression of human IL-6 by mesenchymal cells. Mechanistic studies supported a model whereby IL-6 trans-signaling driven by CD4 T cell–derived soluble IL-6 receptor complexed with fibroblast-derived IL-6 promoted excess extracellular matrix gene expression. Thus, MISTRG6 mice transplanted with scleroderma skin demonstrated multiple fibrotic responses centered around human IL-6 signaling, which was improved by the presence of healthy bone marrow–derived immune cells. Our results highlight the importance of IL-6 trans-signaling in pathogenesis of scleroderma and the ability of healthy bone marrow–derived immune cells to mitigate disease.
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spelling pubmed-105001882023-09-15 IL-6 trans-signaling in a humanized mouse model of scleroderma Odell, Ian D. Agrawal, Kriti Sefik, Esen Odell, Anahi V. Caves, Elizabeth Kirkiles-Smith, Nancy C. Horsley, Valerie Hinchcliff, Monique Pober, Jordan S. Kluger, Yuval Flavell, Richard A. Proc Natl Acad Sci U S A Biological Sciences Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC. We identified that scleroderma skin grafts contained both skin and bone marrow–derived human CD4 and CD8 T cells along with human endothelial cells and pericytes. Unlike healthy skin, fibroblasts in scleroderma skin were depleted and replaced by mouse fibroblasts. Furthermore, HSC engraftment alleviated multiple signatures of fibrosis, including expression of collagen and interferon genes, and proliferation and activation of human T cells. Fibrosis improvement correlated with reduced markers of T cell activation and expression of human IL-6 by mesenchymal cells. Mechanistic studies supported a model whereby IL-6 trans-signaling driven by CD4 T cell–derived soluble IL-6 receptor complexed with fibroblast-derived IL-6 promoted excess extracellular matrix gene expression. Thus, MISTRG6 mice transplanted with scleroderma skin demonstrated multiple fibrotic responses centered around human IL-6 signaling, which was improved by the presence of healthy bone marrow–derived immune cells. Our results highlight the importance of IL-6 trans-signaling in pathogenesis of scleroderma and the ability of healthy bone marrow–derived immune cells to mitigate disease. National Academy of Sciences 2023-09-05 2023-09-12 /pmc/articles/PMC10500188/ /pubmed/37669366 http://dx.doi.org/10.1073/pnas.2306965120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Odell, Ian D.
Agrawal, Kriti
Sefik, Esen
Odell, Anahi V.
Caves, Elizabeth
Kirkiles-Smith, Nancy C.
Horsley, Valerie
Hinchcliff, Monique
Pober, Jordan S.
Kluger, Yuval
Flavell, Richard A.
IL-6 trans-signaling in a humanized mouse model of scleroderma
title IL-6 trans-signaling in a humanized mouse model of scleroderma
title_full IL-6 trans-signaling in a humanized mouse model of scleroderma
title_fullStr IL-6 trans-signaling in a humanized mouse model of scleroderma
title_full_unstemmed IL-6 trans-signaling in a humanized mouse model of scleroderma
title_short IL-6 trans-signaling in a humanized mouse model of scleroderma
title_sort il-6 trans-signaling in a humanized mouse model of scleroderma
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500188/
https://www.ncbi.nlm.nih.gov/pubmed/37669366
http://dx.doi.org/10.1073/pnas.2306965120
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