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Molecular Mechanism of M2 Macrophage-Derived Extracellular Vesicles in Alleviating Inflammation in Rats with Spinal
Junjie Li1, Shuhan Liang2, Jinxin Luo1
1Department of Spine Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.
Abstract:
Spinal cord injury (SCI) is a severe condition with high disability. We aimed to explore the role and mechanism of M2-EVs in SCI-induced inflammation in rats, providing novel treatment methods for SCI. Primary macrophages were differentiated into M2 macrophages. M2-EVs were extracted, followed by morphology detection and measurement of CD63, TSG101, and Calnexin. SCI rats were injected with M2-EVs, followed by assessment of hind limb motor ability, pathological changes, nerve cell morphology, and proinflammatory factor expression. LPS-stimulated spinal astrocytes were treated with M2-EVs. Cell viability, ROS levels, LDH and MDA contents, the expression of lncRNA FTX, FTX, KDM3A, and KLF3, the binding of FTX to KDM3A, and KDM3A enrichment and H3K9me2 on the KLF3 promoter were detected. Results exhibited that M2-EVs treatment increased BBB score, recovered the damaged spinal cord structure, reduced neuronal loss and proinflammatory factor expression. M2-EVs treatment increased cell viability and decreased inflammation. Mechanistically, M2-EVs delivered FTX into cells. FTX bound to KDM3A and inhibited KLF3 expression via blocking H3K9me2 demethylation. KDM3A and KLF3 overexpression partially reversed the inhibitory effect of M2-EVs on inflammation in SCI. In conclusion, M2-EVs suppress SCI inflammation by delivering FTX into cells and inhibiting the KDM3A/KLF3 axis.
Insights
Mesenchymal stem cell-derived extracellular vesicles (M2-EVs) show potential in treating spinal cord injury (SCI). These M2-EVs reduce inflammation and improve motor function by delivering FTX to inhibit the KDM3A/KLF3 axis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Spinal cord injury (SCI) results in significant disability and inflammation.
- Current treatments for SCI have limitations in addressing inflammation and promoting recovery.
Purpose of the Study:
- To investigate the therapeutic potential and underlying mechanisms of M2-EVs in mitigating SCI-induced inflammation in a rat model.
- To elucidate the role of the FTX/KDM3A/KLF3 axis in M2-EV-mediated anti-inflammatory effects.
Main Methods:
- M2-EVs were isolated from M2 macrophages and characterized.
- SCI rats were treated with M2-EVs, and outcomes including motor function, histology, and inflammatory markers were assessed.
- In vitro studies involved LPS-stimulated astrocytes treated with M2-EVs to analyze cell viability, oxidative stress, and molecular pathways (FTX, KDM3A, KLF3).
Main Results:
- M2-EV treatment significantly improved hind limb motor function (BBB score) and spinal cord tissue recovery in SCI rats.
- M2-EVs reduced neuronal loss and suppressed the expression of pro-inflammatory factors.
- Mechanistically, M2-EVs delivered FTX, which inhibited KDM3A/KLF3 expression, thereby reducing inflammation in both in vivo and in vitro models.
Conclusions:
- M2-EVs represent a promising therapeutic strategy for SCI by suppressing inflammation.
- The anti-inflammatory effect of M2-EVs is mediated through the delivery of FTX, which targets the KDM3A/KLF3 signaling pathway.
