Wang Bei-Ni, Du An-Yu, Chen Xiang-Hang, Huang Ting, Mamun Abdullah Al, Li Ping, Du Si-Ting, Feng Yan-Zheng, Jiang Lin-Yuan, Xu Jie, Wang Yu, Wang Shuang-Shuang, Kim Kwonseop, Zhou Kai-Liang, Wu Yan-Qing, Hu Si-Wang, Xiao Jian
Department of Arthroplasty, The First People's Hospital of Wenling, Affiliated Wenling Hospital, Wenzhou Medical University, Taizhou, 317500, China.
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Acta Pharmacol Sin. 2025 May;46(5):1205-1220. doi: 10.1038/s41401-024-01463-w. Epub 2025 Jan 29.
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.
脊髓损伤（SCI）是中枢神经系统（CNS）的一种严重创伤。SCI会诱导形成一种独特的富含脂质的环境，导致大量脂滴（LDs）沉积。已证明LDs的存在会促进其他疾病的进展。脂质自噬是一种选择性自噬类型，参与细胞内LDs的降解。脂肪酸转运蛋白CD36是一种多功能跨膜蛋白，可促进长链脂肪酸的摄取，与某些代谢疾病的进展有关，并对自噬起负调节作用。然而，SCI中LDs产生和降解的确切机制，以及CD36是否通过脂质自噬调节SCI，仍然未知。在本研究中，我们研究了小胶质细胞中LDs积累在SCI中的作用，以及CD36在体内和体外LDs清除过程中对小胶质细胞脂质自噬的调节机制。通过在T9 - T10水平对小鼠脊髓施加适度压迫诱导SCI。在损伤后的第0、1、3、7和14天评估运动恢复情况。将PA刺激的BV2细胞建立为体外脂质负载模型。我们观察到SCI后损伤部位的小胶质细胞中LDs明显积累。更重要的是，含有过量LDs的小胶质细胞表现出激活增强并刺激炎症反应，这极大地触发了小胶质细胞的焦亡。此外，我们发现SCI后小胶质细胞中CD36表达显著增加，脂质自噬被破坏。磺基 - N - 琥珀酰亚胺油酸酯钠（SSO）是一种CD36抑制剂，已证明可促进SCI小鼠和PA处理的BV2细胞中小胶质细胞的脂质自噬，增强LDs降解，改善小胶质细胞的炎症水平和焦亡，最终促进SCI恢复。正如预期的那样，用巴弗洛霉素A1（Baf - A1）抑制自噬可逆转SSO的作用。我们得出结论，小胶质细胞脂质自噬对于SCI恢复过程中LDs的清除至关重要。我们的研究表明，CD36可能是SCI治疗和管理的潜在治疗靶点。
