Neutralization of HMGB1 improves fracture healing and γδ T lymphocyte counts at the fracture site in a polytrauma rat model

Preeti J. Muire, Joshua J. Avila, Alicia L. Lofgren, Joseph C. Wenke

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Purpose: Delayed fracture healing is a common consequence of polytrauma (PT) occurring in patients with multiple injuries. We believe that when early release of high mobility group box 1 (HMGB1) molecules from necrotic tissues exceed their normal levels in blood, they dysregulate immune responses associated with normal healing. This study investigates the detrimental effect of such dysregulate immune responses by targeting HMGB1 in a PT rat model with debilitating injuries. We hypothesized that neutralization of extracellular HMGB1 immediately post-trauma would ameliorate local immune dysregulation and improve fracture healing in a PT rat model. Methods: PT rats received a single dose of either anti-rat HMGB1 polyclonal antibody (PT-Ab HMGB1) or IgY isotype (PT-IgY), were left untreated (PT-C), or had a single injury/osteotomy only (OST). Fracture healing was evaluated by micro-computed tomography (µCT) and histology at 5 weeks; and macrophages and T cell counts within the fracture site were determined with flow cytometry at 1 week. Results: Notably, bone regeneration within the fracture site in PT-Ab HMGB1 rats was improved with comparable connective tissue organization than PT-C rats. Further, only γδTCR+ T cells, but not macrophages and CD4+ and CD8+ T cells, were diminished at the fracture site in PT-C and PT-IgY rats. Interestingly, the PT-Ab HMGB1 rats had increased γδTCR+ T cells compared to PT-C and PT-IgY, suggesting their potential role in regulating fracture healing. Conclusions: Therefore, the initial burst of systemic HMGB1 following trauma may have a role in regulating bone regeneration via the modulation of a subclass of T cells within the fracture site, suggesting it’s importance as a therapeutic target in PT to combat immune dysregulation and delayed fracture healing.

Original languageEnglish (US)
Article number21
JournalJournal of Experimental Orthopaedics
Volume9
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Keywords

  • DAMPs
  • Delayed fracture healing
  • Osteoimmunology
  • Severe trauma

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

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