2. Academic Validation
  3. Inhibition of CD36 ameliorates mouse spinal cord injury by accelerating microglial lipophagy

Inhibition of CD36 ameliorates mouse spinal cord injury by accelerating microglial lipophagy

  • Acta Pharmacol Sin. 2025 Jan 29. doi: 10.1038/s41401-024-01463-w.
Bei-Ni Wang # 1 2 3,  An-Yu Du # 1 2,  Xiang-Hang Chen # 2,  Ting Huang 2,  Abdullah Al Mamun 4,  Ping Li 2,  Si-Ting Du 2,  Yan-Zheng Feng 2,  Lin-Yuan Jiang 2,  Jie Xu 2,  Yu Wang 2,  Shuang-Shuang Wang 1,  Kwonseop Kim 3,  Kai-Liang Zhou 5,  Yan-Qing Wu 6,  Si-Wang Hu 7,  Jian Xiao 8 9
Affiliations

Affiliations

  • 1 Department of Arthroplasty, The First People's Hospital of Wenling, Affiliated Wenling Hospital, Wenzhou Medical University, Taizhou, 317500, China.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • 4 Central Laboratory of The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui People's Hospital, Lishui, 323000, China.
  • 5 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. zhoukailiang@wmu.edu.cn.
  • 6 The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China. yqwu220946@yeah.net.
  • 7 Department of Arthroplasty, The First People's Hospital of Wenling, Affiliated Wenling Hospital, Wenzhou Medical University, Taizhou, 317500, China. siwang_h@wmu.edu.cn.
  • 8 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. xfxj2000@126.com.
  • 9 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. xfxj2000@126.com.
  • # Contributed equally.
PMID: 39880928 DOI: 10.1038/s41401-024-01463-w
Abstract

Spinal cord injury (SCI) is a serious trauma of the central nervous system (CNS). SCI induces a unique lipid-dense environment that results in the deposition of large amounts of lipid droplets (LDs). The presence of LDs has been shown to contribute to the progression of Other Diseases. Lipophagy, a selective type of Autophagy, is involved in intracellular LDs degradation. Fatty acid translocase CD36, a multifunctional transmembrane protein that facilitates the uptake of long-chain fatty acids, is implicated in the progression of certain metabolic diseases, and negatively regulates Autophagy. However, the precise mechanisms of LDs generation and degradation in SCI, as well as whether CD36 regulates SCI via lipophagy, remain unknown. In this study, we investigated the role of LDs accumulation in microglia for SCI, as well as the regulatory mechanism of CD36 in microglia lipophagy during LDs elimination in vivo and in vitro. SCI was induced in mice by applying moderate compression on spina cord at T9-T10 level. Locomotion recovery was evaluated at days 0, 1, 3, 7 and 14 following the injury. PA-stimulated BV2 cells was established as the in vitro lipid-loaded model. We observed a marked buildup of LDs in microglial cells at the site of injury post-SCI. More importantly, microglial cells with excessive LDs exhibited elevated activation and stimulated inflammatory response, which drastically triggered the Pyroptosis of microglial cells. Furthermore, we found significantly increased CD36 expression, and the breakdown of lipophagy in microglia following SCI. Sulfo-N-succinimidyl oleate sodium (SSO), a CD36 inhibitor, has been shown to promote the lipophagy of microglial cells in SCI mice and PA-treated BV2 cells, which enhanced LDs degradation, ameliorated inflammatory levels and Pyroptosis of microglial cells, and ultimately promoted SCI recovery. As expected, inhibition of lipophagy with Baf-A1 reversed the effects of SSO. We conclude that microglial lipophagy is essential for the removal of LDs during SCI recovery. Our research implies that CD36 could be a potential therapeutic target for the treatment and management of SCI.

Keywords

CD36; lipid droplets; lipophagy; microglia; spinal cord injury; sulfo-N-succinimidyl oleate sodium.

Figures
Products