Interleukin 18 as a coupling factor between the inflammatory and the regenerative phase of bone fracture healing

• Applicant: Professorin Dr. Melanie Haffner-Luntzer
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570163107

Fracture healing is a highly complex, multi-phase process characterized by an initial inflammatory phase, followed by a regenerative phase and a subsequent remodeling phase. Particularly, the early inflammatory response—marked by an initial pro-inflammatory and later anti-inflammatory dynamic—acts as a critical determinant for successful tissue regeneration. However, the underlying molecular mechanisms orchestrating the transition from inflammation to regeneration remain poorly understood. Our preliminary data suggest that interleukin-18 (IL-18) may play a pivotal role as a “coupling factor” between the inflammatory and regenerative phases of fracture healing. In a clinical pilot study involving patients with ankle fractures, we identified IL-18 in the fracture hematoma as one of the cytokines whose concentration significantly correlated with the healing outcome. Complementary in vitro analyses using human mesenchymal stromal cells (MSCs) demonstrated that IL-18 priming induces a pro-regenerative transcriptional profile in these cells. Furthermore, using our established mouse femur fracture model, we were able to show that myeloid-derived suppressor cells (MDSCs) represent a major source of IL-18 in the early fracture hematoma. Through the production of IL-18, these cells may exert immunomodulatory functions while simultaneously initiating regenerative processes. Based on these findings, the central hypothesis of the proposed project is that IL-18 acts as a key coupling factor between inflammation and tissue regeneration during fracture healing. We hypothesize that IL-18 is secreted by MDSCs, which not only modulates inflammation but also primes MSCs towards a pro-regenerative phenotype. This proposal aims to pursue two main research objectives: 1. Characterization of MDSCs and their role in fracture healing: Single-cell RNA sequencing (scRNASeq) will be employed to identify MDSC subpopulations and IL-18-producing cells in the early fracture hematoma in mice. Additionally, in vivo transfer experiments using MDSCs derived from wild-type and IL-18 knockout mice will be conducted to assess their functional role in fracture healing. 2. Evaluation of the therapeutic potential of IL-18 and IL-18-primed MSCs: In a murine fracture model with a critical-size defect, the efficacy of recombinant IL-18 as a cell-free therapeutic strategy will be investigated. Furthermore, IL-18-primed MSCs will be evaluated as a cell-based therapeutic approach. Both strategies will be analyzed with regard to their effects on inflammation, regeneration, and overall healing success using advanced methodologies such as scRNASeq, spatial transcriptomics, biomechanical testing, and high-resolution imaging techniques.

• DFG Programme: Research Grants
• International Connection: USA
• Co-Investigator: Professorin Dr. Gudrun Strauß
• Cooperation Partner: Professor Dr. Philipp Leucht, Ph.D.