AXL-Induced Autophagy mitigates experimental autoimmune encephalomyelitis by suppressing microglial inflammation via the PI3K/AKT/mTOR signaling pathway
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Updated: Jul 28, 2025
Author Spotlight: Creating a Versatile Experimental Autoimmune Encephalomyelitis Model Relevant for Both Male and Female Mice
Published on: October 13, 2023
Mengjiao Sun1, Panpan Gong2, Boyao Yuan1
1Department of Neurology, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan District, Lanzhou 730030, China.
Abstract:
Microglia, being the primary immune cells of the central nervous system (CNS), are responsible for pathological inflammatory demyelination in multiple sclerosis (MS). It has been demonstrated that AXL, one of the receptor tyrosine kinases, could alleviate the inflammatory response of microglia. However, the specific mechanism remains unclear. Herein, we explored the role of AXL in the autophagy of microglia and its effect on the experimental autoimmune encephalomyelitis (EAE) model. We revealed that knockout of AXL in BV2 microglia significantly promoted the expression of phosphorylated-PI3K/p-AKT/p-mTOR while significantly inhibiting LC3-Ⅱ/Beclin1. Similarly, autophagy was significantly inhibited in the AXL-/- mice. Knockout of AXL induced serious symptoms, infiltration of inflammatory cells, and demyelination changes, manifesting as the upregulation of pro-inflammatory factors TNF-α and IL-6 and downregulation of anti-inflammatory factors TGF-β and IL-10. In conclusion, this study substantiated that autophagy induced by AXL inhibited the inflammatory response of microglia and alleviated symptoms of EAE. Autophagy activation was mediated by the PI3K/AKT/mTOR signaling pathway.
Insights
AXL receptor tyrosine kinase activates autophagy in microglia, reducing inflammation and demyelination in multiple sclerosis models. This pathway, mediated by PI3K/AKT/mTOR, offers a potential therapeutic target for central nervous system inflammatory diseases.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Molecular Medicine
Background:
- Microglia are key immune cells in the central nervous system (CNS), driving inflammatory demyelination in multiple sclerosis (MS).
- AXL, a receptor tyrosine kinase, is known to modulate microglial inflammatory responses, but its precise mechanism is not fully understood.
Purpose of the Study:
- To investigate the role of AXL in microglial autophagy.
- To determine the impact of AXL on the experimental autoimmune encephalomyelitis (EAE) model of MS.
Main Methods:
- Utilized BV2 microglia cell line and AXL knockout (AXL-/-) models.
- Analyzed autophagy markers (LC3-II/Beclin1) and the PI3K/AKT/mTOR signaling pathway.
- Assessed clinical symptoms, inflammatory cell infiltration, and demyelination in EAE mice.
Main Results:
- AXL knockout in microglia significantly inhibited autophagy, evidenced by reduced LC3-II/Beclin1 expression.
- AXL deficiency led to increased PI3K/AKT/mTOR pathway activity, suggesting its role in regulating autophagy.
- AXL-/- mice exhibited exacerbated EAE symptoms, increased pro-inflammatory cytokines (TNF-α, IL-6), and reduced anti-inflammatory cytokines (TGF-β, IL-10).
Conclusions:
- AXL-induced autophagy suppresses microglial inflammatory responses.
- Activation of the PI3K/AKT/mTOR pathway mediates AXL's effect on autophagy.
- Targeting AXL-mediated autophagy presents a potential therapeutic strategy for mitigating MS-related neuroinflammation and demyelination.
