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

Abstract

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including  T cells and Th17 cells. However, the origin and relevance for fracture repair of these T cells are unknown. Here we show that fractures rapidly expanded callus  T cells, which led to increased gut permeability by promoting systemic inflammation.When the microbiota contained the Th17 cell-inducing taxa segmented filamentous bacteria (SFB), activation of  T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improvement of fracture repair. Mechanistically, fractures increased the S1Preceptor-1 (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  T cells, depletion of the microbiome by antibiotics, blockade of Th17 cell egress from the gut or antibody neutralization of Th17 cell influx into the callus. These findings demonstrated 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 antibiotics may represent novel therapeutic strategies to optimize fracture healing.

T cells heal bone fractures with help from the gut microbiome

“…Finally, inhibition of the recruitment of T cells led to a delay in bone callus formation at day 14, and the repaired bone had reduced biomechanical properties at day 35. These results confirm that the repair process is serialized and that events in early stages of healing delay or prevent later stages and affect the functional quality of the repaired bone ( 6 ).…”

“…For example, gut microbiota can affect bone loss following ovariectomy in a model of postmenopausal osteoporosis ( 22 ) and also influence the anabolic effect of the FDA-approved parathyroid hormone used to treat osteoporosis ( 23 ). Dar et al extend this work and propose a model whereby the gut microbiome regulated, in part, the inflammatory phase of fracture healing ( Figure 1 ) ( 6 ). Bone fractures release sphingosine-1-phosphate (S1P) to recruit T cells.…”

“…While these stages provide a helpful conceptual framework, it is recognized that the pace of events within and between stages varies spatially and that aspects of each stage may be present together within a fracture callus. In this issue of the JCI , Dar et al primarily examined immune cell and cytokine responses at day three, corresponding to the initial inflammatory phase, followed by functional outcomes at the end of bony callus formation at days 14 and 21 and remodeling at day 35 ( 6 ).…”

“…Recently, Ono et al reported that γδ T cells are present at the site of bone injury and that IL-17A from these cells promotes bone formation in the defect ( 14 ). Dar et al extended this work to focus on the effects and origins of T cells, both αβ and γδ subtypes, in a more clinically relevant model of full fracture that heals via endochondral ossification ( 6 ). αβ T cells are activated via T cell receptor (TCR) binding to antigen in the context of the MHC of antigen-presenting cells (APCs).…”

“…Dar et al introduced segmented filamentous bacteria (SFB) into mice. SFB are a host-adapted genetic cousin of the genus Clostridium that bind to absorptive epithelium cells ( 6 ). While SFB are commensals, they, uniquely, induce a response from IL-17–expressing CD4 + T cells (Th17) when introduced into a naive host.…”