Tauroursodeoxycholic acid regulates macrophage/monocyte distribution and improves spinal microenvironment to promote nerve regeneration through inhibiting NF-κB signaling pathway in spinal cord injury

Yonghui Hou; Yage Zhang; Lin Ma; Dan Luo; Wanshun Wang; Shunmei E; Chengxi Huang; Yu Hou; Shudong Chen; Jiheng Zhan; Liangliang Xu; Dingkun Lin

doi:10.3389/fphar.2025.1554945

Tauroursodeoxycholic acid regulates macrophage/monocyte distribution and improves spinal microenvironment to promote nerve regeneration through inhibiting NF-κB signaling pathway in spinal cord injury

Front Pharmacol. 2025 Apr 10:16:1554945. doi: 10.3389/fphar.2025.1554945. eCollection 2025.

Authors

Yonghui Hou^{1

2}, Yage Zhang^{2

3}, Lin Ma^{2

4}, Dan Luo^{1

2}, Wanshun Wang^{1

2}, Shunmei E⁵, Chengxi Huang⁶, Yu Hou^{1

2}, Shudong Chen^{1

2}, Jiheng Zhan^{1

2}, Liangliang Xu^{2

3}, Dingkun Lin^{1

2}

Affiliations

¹ Department of Orthopedic Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
² Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
³ Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁴ College of Physical Education and Health, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁵ Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong, China.
⁶ Culver Academies, Culver, IN, United States.

Abstract

Introduction: Following spinal cord injury (SCI), blood-borne monocytes infiltrate the spinal cord, differentiate into macrophages, and dominate the lesion site. Inflammatory responses mediated by macrophages determine nerve regeneration and functional recovery after SCI. Tauroursodeoxycholic acid (TUDCA) shows a neuroprotective effect in different SCI animal models. However, the underlying mechanism of TUDCA regulating monocytes/macrophages to impact nerve regeneration after SCI has not been elucidated clearly. This study aims to investigate the effect of TUDCA on monocyte/macrophage distribution and nerve regeneration in the subacute stage of SCI.

Methods: Transwell analysis, Bromodeoxyuridine (BrdU) staining, and TUNEL staining were performed to evaluate the effect of TUDCA on regulating the inflammatory response to impact spinal neural stem cells (NSCs) proliferation and migration, spinal neuron survival, and axon degeneration in vitro. H&E staining, RNA sequencing, and a series of immunofluorescent staining were performed to investigate the pathological progress, gene expression changes, monocytes/macrophages distribution, and nerve regeneration after TUDCA treatment in SCI mice.

Results: We found TUDCA restored spinal NSCs migration and proliferation and reduced spinal NSCs and neurons apoptosis and axon degeneration by regulating inflammatory response in vitro. TUDCA treatment promoted wound healing, down-regulated genes related to inflammatory response, and up-regulated genes related to spinal cord development in SCI mice.

Conclusions: Our study provided evidence that TUDCA treatment regulated monocyte/macrophage distribution and improved the microenvironment to promote nerve regeneration in SCI mice.

Keywords: inflammation; macrophage; microenvironment; monocyte; nerve regeneration; spinal cord injury; tauroursodeoxycholic acid.