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Updated: Apr 19, 2026
Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
Aldose Reductase Regulates Microglia/Macrophages Polarization Through the cAMP Response Element-Binding Protein After
Qian Zhang1, Ganlan Bian1, Peng Chen1
1Department of Neurobiology, The Fourth Military Medical University, 169 West Changle Road, Xi'an, 710032, China.
Abstract:
Inflammatory reactions are the most critical pathological processes occurring after spinal cord injury (SCI). Activated microglia/macrophages have either detrimental or beneficial effects on neural regeneration based on their functional polarized M1/M2 subsets. However, the mechanism of microglia/macrophage polarization to M1/M2 at the injured spinal cord environment remains unknown. In this study, wild-type (WT) or aldose reductase (AR)-knockout (KO) mice were subjected to SCI by a spinal crush injury model. The expression pattern of AR, behavior tests for locomotor activity, and lesion size were assessed at between 4 h and 28 days after SCI. We found that the expression of AR is upregulated in microglia/macrophages after SCI in WT mice. In AR KO mice, SCI led to smaller injury lesion areas compared to WT. AR deficiency-induced microglia/macrophages induce the M2 rather than the M1 response and promote locomotion recovery after SCI in mice. In the in vitro experiments, microglia cell lines (N9 or BV2) were treated with the AR inhibitor (ARI) fidarestat. AR inhibition caused 4-hydroxynonenal (HNE) accumulation, which induced the phosphorylation of the cAMP response element-binding protein (CREB) to promote Arg1 expression. KG501, the specific inhibitor of phosphorylated CREB, could cancel the upregulation of Arg1 by ARI or HNE stimulation. Our results suggest that AR works as a switch which can regulate microglia by polarizing cells to either the M1 or the M2 phenotype under M1 stimulation based on its states of activity. We suggest that inhibiting AR may be a promising therapeutic method for SCI in the future.
Insights
Inhibiting aldose reductase (AR) promotes M2 microglia polarization and locomotor recovery after spinal cord injury (SCI). AR deficiency reduces lesion size and enhances neural regeneration, offering a potential therapeutic strategy for SCI.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Spinal cord injury (SCI) triggers inflammatory responses involving microglia/macrophages.
- Microglia/macrophage polarization into M1 (detrimental) or M2 (beneficial) phenotypes critically impacts neural regeneration after SCI.
- The precise mechanisms governing microglia/macrophage polarization in the SCI environment are not fully understood.
Purpose of the Study:
- To investigate the role of aldose reductase (AR) in microglia/macrophage polarization following SCI.
- To determine if modulating AR activity can influence functional recovery and lesion size after SCI.
- To elucidate the molecular pathways by which AR affects microglia polarization.
Main Methods:
- Spinal crush injury model in wild-type (WT) and aldose reductase-knockout (AR KO) mice.
- Assessment of locomotor activity, lesion size, and AR expression post-SCI.
- In vitro studies using microglia cell lines treated with an AR inhibitor (fidarestat) and pathway inhibitors (KG501).
Main Results:
- AR expression was upregulated in microglia/macrophages after SCI in WT mice.
- AR KO mice exhibited smaller lesion areas and improved locomotor recovery compared to WT mice.
- AR inhibition in vitro promoted M2 microglia polarization (indicated by Arg1 expression) via 4-hydroxynonenal (HNE) and CREB phosphorylation.
Conclusions:
- Aldose reductase (AR) acts as a regulatory switch for microglia/macrophage polarization in the context of SCI.
- Inhibiting AR promotes a shift towards the beneficial M2 phenotype, reducing inflammation and enhancing functional recovery.
- Targeting AR presents a promising therapeutic avenue for managing spinal cord injury.
