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Hv1 upregulation worsens spinal, spleen, and lung molecular pathology and impairs locomotion after spinal cord injury in aged male mice

ABSTRACT: Spinal cord injury (SCI) induces both intraspinal damage and systemic organ pathology, with aging as a major determinant of outcome. However, how advanced age exacerbates SCI pathology remains unclear. The voltage-gated proton channel Hv1, a regulator of immune activation, increases with age and after SCI, and its deletion is neuroprotective in young mice. Thus, we hypothesized that age-related Hv1 upregulation worsens spinal cord, spleen, and lung pathology and hinders locomotor recovery after SCI through immune modulation. Using aged Hv1 KO and WT male mice subjected to moderate SCI, we assessed behavioral and molecular outcomes. Transcriptomic analysis revealed that Hv1 mRNA expression was higher in the brains of aged sham mice and further upregulated in injured spinal cord tissues. Spinal cord RNA-seq showed acute innate immune and cytokine activation in both genotypes. Hv1 deletion enhanced chromatin remodeling, epigenetic and Wnt signaling, while suppressing NF-κB–driven inflammation and oxidative stress–induced apoptosis. In the spleen, Hv1 depletion enhanced immune responses while suppressing mitosis. T cell and leukocyte activation increased, whereas lung cytokine signaling decreased. At 6 weeks after SCI, Hv1 KO mice showed elevated expression of genes related to circadian rhythm and T cell proliferation in the spinal cord, increased mitotic gene expression but reduced adaptive immunity in the spleen, and enhanced immune activation with decreased cilium activity in the lungs.

ORGANISM(S): Mus musculus

PROVIDER: GSE313209 | GEO | 2025/12/17

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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Hv1 upregulation worsens spinal, spleen, and lung molecular pathology and impairs locomotion after spinal cord injury in aged male mice

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