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

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.