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Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus γδ T...

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Autores principales: Dar, Hamid Y., Perrien, Daniel S., Pal, Subhashis, Stoica, Andreea, Uppuganti, Sasidhar, Nyman, Jeffry S., Jones, Rheinallt M., Weitzmann, M. Neale, Pacifici, Roberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104897/
https://www.ncbi.nlm.nih.gov/pubmed/36881482
http://dx.doi.org/10.1172/JCI166577
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author Dar, Hamid Y.
Perrien, Daniel S.
Pal, Subhashis
Stoica, Andreea
Uppuganti, Sasidhar
Nyman, Jeffry S.
Jones, Rheinallt M.
Weitzmann, M. Neale
Pacifici, Roberto
author_facet Dar, Hamid Y.
Perrien, Daniel S.
Pal, Subhashis
Stoica, Andreea
Uppuganti, Sasidhar
Nyman, Jeffry S.
Jones, Rheinallt M.
Weitzmann, M. Neale
Pacifici, Roberto
author_sort Dar, Hamid Y.
collection PubMed
description IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus γδ T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell–inducing taxon segmented filamentous bacteria (SFB), activation of γδ T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1–mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of γδ T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell–inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing.
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spelling pubmed-101048972023-04-17 Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice Dar, Hamid Y. Perrien, Daniel S. Pal, Subhashis Stoica, Andreea Uppuganti, Sasidhar Nyman, Jeffry S. Jones, Rheinallt M. Weitzmann, M. Neale Pacifici, Roberto J Clin Invest Research Article IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus γδ T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell–inducing taxon segmented filamentous bacteria (SFB), activation of γδ T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1–mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of γδ T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell–inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing. American Society for Clinical Investigation 2023-04-17 /pmc/articles/PMC10104897/ /pubmed/36881482 http://dx.doi.org/10.1172/JCI166577 Text en © 2023 Dar et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Dar, Hamid Y.
Perrien, Daniel S.
Pal, Subhashis
Stoica, Andreea
Uppuganti, Sasidhar
Nyman, Jeffry S.
Jones, Rheinallt M.
Weitzmann, M. Neale
Pacifici, Roberto
Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
title Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
title_full Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
title_fullStr Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
title_full_unstemmed Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
title_short Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
title_sort callus γδ t cells and microbe-induced intestinal th17 cells improve fracture healing in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104897/
https://www.ncbi.nlm.nih.gov/pubmed/36881482
http://dx.doi.org/10.1172/JCI166577
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