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  3. Targeting RXRα inhibits foamy macrophage formation and neuroinflammation by promoting cholesterol efflux channels post traumatic spinal cord injury

Targeting RXRα inhibits foamy macrophage formation and neuroinflammation by promoting cholesterol efflux channels post traumatic spinal cord injury

  • Int Immunopharmacol. 2026 Jan 1;168(Pt 2):115945. doi: 10.1016/j.intimp.2025.115945.
Rulin Li 1,  Qihao Fu 2,  Zeyu Jiang 1,  Jian Zhou 2,  Chaoqiang Zhang 2,  Boquan Shan 3,  Lijia Ge 3,  Guanhua Xu 4,  Haijun Li 5,  Zhanyang Qian 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China.
  • 2 Department of Orthopedics, Nantong First People's Hospital; Nantong 226001, China; Research Institute for Spine and Spinal Cord Disease of Nantong University, Nantong, China, Nantong 226001, China.
  • 3 Medical Research Center, Nantong First People's Hospital, Nantong, 226001, China.
  • 4 Department of Orthopedics, Nantong First People's Hospital; Nantong 226001, China. Electronic address: [email protected].
  • 5 Department of Orthopedics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China. Electronic address: [email protected].
  • 6 Department of Orthopedics, Nantong First People's Hospital; Nantong 226001, China; Research Institute for Spine and Spinal Cord Disease of Nantong University, Nantong, China, Nantong 226001, China; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, Jiangsu 226001, China. Electronic address: [email protected].
PMID: 41317538 DOI: 10.1016/j.intimp.2025.115945
Abstract

The formation of foamy cells (FMMs) by excessive engulfment of myelin debris (MD) causes secondary neuroinflammation and chronic neuropathies after traumatic spinal cord injury (SCI). It is unclear what the function and mechanism of retinoid X receptor (RXR) α are in FMMs-induced neuroinflammation and neural improvement post SCI. The present study aims to investigate the effects and underlying mechanisms of RXRα activation on FMMs and SCI mice. We established an in vitro FMMs model by MD stimulation and an in vivo SCI model in mice. Using an agonist 2, 4-Di-tert-butylphenol (2, 4-DTBP), we activated RXRα and examined the inflammation levels by PCR, WB, and Immunofluorescence (IF), then detected lipid accumulation by BODIPY and Oil red O staining, and determined secondary neuropathies using IF and histological staining. The locomotor function recovery was assessed using motor evoked potential (MEP), Basso Mouse Scale (BMS), as well as footprint assay. Activation of RXRα by 2, 4-DTBP reduced the expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and the levels of inflammatory mediators iNOS and COX-2. Besides, treatment with 2, 4-DTBP increased the expression of Cholesterol efflux channels including Abca1, Abcg1, apoE, and caused a marked decrease in intracellular Cholesterol and lipid accumulation. Blocking the RXRα-induced Cholesterol efflux caused an increase in Cholesterol and FMMs, reversing the prior decrease, and exacerbated the degree of neuroinflammation. Also, administration of 2, 4-DTBP improved the neuropathies and locomotor function recovery after SCI.Taken together, activation of RXRα decreased the formation of FMMs by promoting Cholesterol efflux and inhibited neuroinflammation by inhibition of p38 and NF-κB signaling after SCI. It is a promising target for mitigating FMMs-induced neuroinflammation and locomotor dysfunction.

Keywords

Foamy cell; Lipid; Neuroinflammation; RXRα; Spinal cord injury.

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