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Treg-microglia partnership in the injured spinal cord preserves Treg cells function and regulates microglial cholesterol metabolism

ABSTRACT: The quantitative variations and specific roles of regulatory T cells (Treg cells) within spinal cord injury (SCI) remain elusive. Utilizing single-cell RNA sequencing, flow cytometry, and immunofluorescence, we discovered that Treg cells began to infiltrate the injured spinal cords in mice approximately three days after SCI. Selective depletion of Treg cells resulted in an expansion of the injury area, reduction in neuronal survival, and a decrease in long-term functional recovery post-SCI. Transcriptomic analyses of Treg cells unveiled potent anti-inflammatory functions and the potential to influence neighboring immune cells within the spinal cord after SCI. Adoptive transfer of Treg cells demonstrated measurable improvement in SCI recovery and increased neuronal retention in mice. However, selective depletion of microglia inhibited the neuroprotective effects of Treg cells, indicating that the effect of Treg cells in the spinal cord depends on the presence of microglia. Mechanistically, Treg cells promoted spinal cord functional recovery by upregulating microglial Abcg1 receptor expression, enhancing cholesterol transport, reducing microglial lipid droplet formation, and moderating the M1 phenotype after SCI. In summary, our study elucidates the spatiotemporal distribution of Treg cells after SCI and their unique transcriptomic features, clarifying the impact of Treg cells on microglial cholesterol metabolism and inflammatory phenotype. These findings indicate that Treg cells may serve as a potential target for SCI treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE243607 | GEO | 2025/09/29

REPOSITORIES: GEO

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Project description:The inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed. In this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues. We demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation. Overall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

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Treg-microglia partnership in the injured spinal cord preserves Treg cells function and regulates microglial cholesterol metabolism

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