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

• Published in: The Journal of clinical investigation Vol. 133; no. 8; pp. 1 - 15
• Main Authors: Dar, Hamid Y, Perrien, Daniel S, Pal, Subhashis, Stoica, Andreea, Uppuganti, Sasidhar, Nyman, Jeffry S, Jones, Rheinallt M, Weitzmann, M Neale, Pacifici, Roberto
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 17.04.2023
• Subjects: Animals; Antibiotics; Bacteria; Biomedical research; Bone Biology; Bone healing; Callus; CCL20 protein; Cell activation; Cells; Clonal deletion; Cytokines; Digestive system; Digestive tract; Filamentous bacteria; Fracture Healing; Fractures; Helper cells; Homing behavior; Inflammation; Interleukin 17; Intestine; Ligands; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Microbiology; Microbiomes; Microbiota; Microorganisms; Permeability; Receptors, Antigen, T-Cell, gamma-delta - genetics; Th17 Cells; Bone Biology; Bone disease; Microbiology; T cells; Orthopedics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI166577

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.