2. Academic Validation
  3. AXL Promotes Ischemic Myelin Repair Through Alleviating Myelin Debris Deposition and Lipid Droplets Accumulation

AXL Promotes Ischemic Myelin Repair Through Alleviating Myelin Debris Deposition and Lipid Droplets Accumulation

  • Adv Sci (Weinh). 2026 Feb;13(10):e17825. doi: 10.1002/advs.202517825.
Junqiu Jia 1,  Yonghui Gan 2,  Jia Li 3,  Lilin Li 3,  Hailan Meng 3 4 5 6 7,  Min Sun 3 4 5 6 7,  Lei Ye 3 4 5 6 7,  Rui Mao 3 4 5 6 7,  Xiang Cao 3 4 5 6 7,  Shengnan Xia 3 4 5 6 7,  Xinyu Bao 3 4 5 6 7,  Renyuan Liu 8,  Meijuan Zhang 3 4 5 6 7,  Yun Xu 1 3 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Neurology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China.
  • 2 Department of Emergency Medicine, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
  • 5 Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
  • 6 Jiangsu Provincial Key Discipline of Neurology, Nanjing, China.
  • 7 Nanjing Neurology Clinical Medical Center, and Nanjing Gulou Hospital Brain disease and brain Science Center, Nanjing, China.
  • 8 Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
PMID: 41524160 DOI: 10.1002/advs.202517825
Abstract

Ischemic white matter injury leads to long-term neurological deficits but currently lacks effective therapies. Although Axl has been implicated in debris clearance and inflammatory regulation, its role in post-stroke myelin repair remains unclear. Here, we report robust upregulation of microglial Axl in mice after tMCAO. Microglial Axl cKO mice exhibited worse motor and cognitive deficits up to 28 days after tMCAO, accompanied by more severe white matter damage, increased myelin debris, and greater lipid droplets (LDs) accumulation in microglia than WT controls. Longitudinal analysis showed that AXL-deficient microglia had reduced early phagocytic capacity but increased LDs accumulation and lipid peroxidation at later stages. Transcriptomic profiling revealed altered inflammatory and sphingolipid metabolism pathways in AXL-deficient microglia. Mechanistically, Axl regulates Smpd1 transcription via EGR1, thereby modulating sphingolipid metabolism and LDs accumulation. Remarkably, supplement with ASM (the Smpd1-encoded enzyme) in Axl cKO mice reduced LDs accumulation and attenuated ischemic white matter injury. Collectively, these findings identify microglial Axl as an endogenous regulator of myelin repair after ischemic stroke.

Keywords

AXL; ischemic stroke; lipid droplet; microglia; myelin debris.

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