American Society for Peripheral Nerve
ASPN Home ASPN Home Past & Future Meetings Past & Future Meetings

Back to 2023 Abstracts


FK506-mediated neuroregeneration is dependent on recruited macrophages
Curtis Broberg, BS1; Albina Jablonka-Shariff, PhD2; Snyder-Warwick K Alison, MD3
1Washington University, Saint Louis, MO; 2Plastic Surgery, Washington University School of Medicine, Saint Louis, MO; 3Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO

Introduction: Nerves have the capacity to regenerate through a process in which macrophages play a key role. At the site of injury, macrophages clear nerve debris and promote angiogenesis as well as subsequent nerve regeneration. At the neuromuscular junction (NMJ), macrophages interact with terminal Schwann cells to aid regenerating axon guidance to their target muscle. However, this process is imperfect, with many patients failing to fully recover. Tacrolimus (FK506) treatment speeds functional recovery through unknown mechanisms. The expression of the FK506 binding protein FKBP52 by macrophages and their known roles in the neuroregenerative process makes them a promising candidate for involvement in FK506-mediated NMJ innervation and functional muscle recovery. This study investigated whether macrophages were required for FK506 neuroenhancement.
Materials and Methods: Wildtype (WT) and mice with impaired macrophage recruitment (CCR2-/-) mice were injected subcutaneously with either saline or 2mg/kg/day of FK506 for three days prior to sciatic nerve transection and immediate repair. Daily injections of saline or FK506 were then continued for 4 weeks. Functional recovery was assessed weekly with grid walking assays. At 4 weeks, motor function was tested by extensor digitorum longus (EDL) muscle force analysis. Morphometric analysis of NMJ reinnervation in EDL muscles was also conducted at the study endpoint.
Results: In WT mice, FK506 administration resulted in improvements in reinnervation and functional recovery. FK506-injected WT mice showed increased proportions of fully reinnervated NMJs relative to those injected with saline (mean 75.00 1.26% vs. 52.10 3.24% p=0.0003), as well as improved recovery of tetanic muscle force (mean 20.97 3.86 N/cm2 vs. 15.20 3.07 N/cm2 p=0.0134) and improvement in grid walking (mean 10.98 1.19% faults vs. 16.85 1.94% faults p=0.0111). Enhancements in recovery were not seen in mice with deficient macrophage recruitment (CCR2-/- mice); there were no statistical differences between CCR2-/-mice treated with FK506 compared to saline on any tested metric (P>0.05).
Conclusions: These results show that macrophages are required for FK506-mediated improvements in NMJ reinnervation and function. These data implicate macrophages in the mechanism underlying FK506-mediated enhancement of neuroregeneration


Back to 2023 Abstracts