Recombinant fibroblast growth factor 4 ameliorates axonal regeneration and functional recovery in acute spinal cord injury through altering microglia/macrophage phenotype

Rui Li; Juerong Feng; Liuxun Li; Guotian Luo; Yongpeng Shi; Shichao Shen; Xinrong Yuan; Jianlong Wu; Bin Yan; Lei Yang

doi:10.1016/j.intimp.2024.112188

Recombinant fibroblast growth factor 4 ameliorates axonal regeneration and functional recovery in acute spinal cord injury through altering microglia/macrophage phenotype

Int Immunopharmacol. 2024 May 9:134:112188. doi: 10.1016/j.intimp.2024.112188. Online ahead of print.

Authors

Rui Li¹, Juerong Feng², Liuxun Li², Guotian Luo², Yongpeng Shi², Shichao Shen², Xinrong Yuan², Jianlong Wu², Bin Yan³, Lei Yang⁴

Affiliations

¹ Orthopaedics/Department of Spine Surgery, Department of Pharmacy and Department of Gastroenterology, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
² Orthopaedics/Department of Spine Surgery, Department of Pharmacy and Department of Gastroenterology, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
³ Orthopaedics/Department of Spine Surgery, Department of Pharmacy and Department of Gastroenterology, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China. Electronic address: yanbinzhiyou@163.com.
⁴ Orthopaedics/Department of Spine Surgery, Department of Pharmacy and Department of Gastroenterology, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China. Electronic address: yangl@email.szu.edu.cn.

PMID: 38728880
DOI: 10.1016/j.intimp.2024.112188

Abstract

Neuroinflammation is one of the extensive secondary injury processes that aggravate metabolic and cellular dysfunction and tissue loss following spinal cord injury (SCI). Thus, an anti-inflammatory strategy is crucial for modulating structural and functional restoration during the stage of acute and chronic SCI. Recombinant fibroblast growth factor 4 (rFGF4) has eliminated its mitogenic activity and demonstrated a metabolic regulator for alleviating hyperglycemia in type 2 diabetes and liver injury in non-alcoholic steatohepatitis. However, it remains to be explored whether or not rFGF4 has a neuroprotective effect for restoring neurological disorders, such as SCI. Here, we identified that rFGF4 could polarize microglia/macrophages into the restorative M2 subtype, thus exerting an anti-inflammatory effect to promote neurological functional recovery and nerve fiber regeneration after SCI. Importantly, these effects by rFGF4 were related to triggering PI3K/AKT/GSK3β and attenuating TLR4/NF-κB signaling axes. Conversely, gene silencing of the PI3K/AKT/GSK3β signaling or pharmacological reactivation of the TLR4/NF-κB axis aggravated inflammatory reaction. Thus, our findings highlight rFGF4 as a potentially therapeutic regulator for repairing SCI, and its outstanding effect is associated with regulating macrophage/microglial polarization.

Keywords: Microglia/macrophage polarization; Neuroinflammation; Neuroprotection; Recombinant fibroblast growth factor 4 (rFGF4); Spinal cord injury (SCI).