PHYSIOLOGICAL FRACTURE HEALING IS UNAFFECTED BY NEUTROPHIL-DERIVED IL-6 OR IL-6R SIGNALING IN MICE.

Background : Neutrophils are the predominant immune cell type in the early fracture hematoma, playing key roles in orchestrating the immune response and bone repair by clearing pathogens and debris, producing extracellular traps and proteases, and releasing various signaling molecules. However, neutrophil roles in fracture healing remain incompletely understood. They are a key source of interleukin-6 (IL-6) and the soluble IL-6 receptor (sIL-6R), driving both IL-6 classic signaling via membrane-bound IL-6R and trans-signaling via sIL-6R. Classic signaling drives neutrophil infiltration into the fracture hematoma and is crucial for bone repair, whereas trans-signaling impairs healing after severe trauma. Here, we examined neutrophil-specific IL-6 signaling in fracture healing. Methods : We used male mice with neutrophil-specific deletion of IL-6 or IL-6R . Physiological bone phenotype and effects on fracture healing (external fixator stabilized femur osteotomy) were assessed in 12-week-old mice by flow cytometry, cytokine multiplex analysis, biomechanical testing, micro-computed tomography, and histomorphometry. Results : While neutrophil-specific deletion of IL-6 or IL-6R did not affect bone under physiological conditions, IL-6R deletion led to a reduction in neutrophils and macrophages and an increase in T lymphocytes. The immune response to fracture was unaffected by either deletion, because cytokine levels in the fracture hematoma and serum remained unchanged compared to controls after 6 h. Additionally, the biomechanical properties of fractured femurs together with structural and cellular bone parameters on day 21 did not differ compared to controls. Conclusions : Neutrophil-induced IL-6 signaling appears nonessential for physiological bone turnover and fracture healing. Its role in impaired healing under conditions of excessive inflammation remains to be determined.