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Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states

ABSTRACT: Rehabilitative training is an effective method to promote recovery following spinal cord injury (SCI), with lower training efficacy observed in the chronic stage. The increased training efficacy during the subacute period is associated with an adaptive state induced by the SCI. A potential link is SCI-induced inflammation, which is elevated in the subacute period, and as injection of lipopolysaccharide (LPS) alongside training improves recovery in chronic SCI, suggesting LPS could reopen a window of plasticity late after injury. Microglia may play a role in LPS-mediated plasticity as they react to LPS and are implicated in facilitating recovery following SCI. However, it is unknown how microglia change in response to LPS following SCI to promote neuroplasticity. Here we used single-cell RNA sequencing to examine microglial responses in subacute and chronic SCI with and without an LPS injection. We show that subacute SCI is characterized by a disease-associated microglial (DAM) signature, while chronic SCI is highly heterogeneous, with both injury-induced and homeostatic states. With LPS injection, microglia shifted away from the homeostatic signature to a primed, translation-associated state and increased DAM in degenerated tracts caudal to the injury. Our results contribute to an understanding of how microglia and LPS-induced neuroinflammation contribute to plasticity following SCI.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE281996 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:T cells undergo autoimmunization following spinal cord injury (SCI) and play both protective and destructive roles during the recovery process. T-cell deficient athymic nude (AN) rats recover better than immunocompetent Sprague-Dawley (SD) rats following spinal cord transection. In the present study, we evaluated locomotor recovery in SD and AN rats following moderate spinal cord contusion. To explain variable locomotor outcome, we assessed whole-genome expression using RNA sequencing, in the acute (1 week post-injury) and chronic (8 weeks post-injury) phases of recovery. AN rats demonstrated greater locomotor function than SD rats only at 1 week post-injury, coinciding with peak T cell infiltration in immunocompetent rats. Genetic markers for T cells and helper T cells were acutely enriched in SD rats, while AN rats expressed genes for Th2 cells, cytotoxic T cells, NK cells, mast cells, IL-1a, and IL-6 at higher levels. Acute enrichment of cell death-related genes suggested that SD rats undergo secondary tissue damage from T cells. Additionally, SD rats exhibited increased acute expression of voltage-gated potassium (Kv) channel-related genes. However, AN rats demonstrated greater chronic expression of cell death-associated genes and less expression of axon-related genes. We put forth a model in which T cells facilitate early tissue damage, demyelination, and Kv channel dysregulation in SD rats following contusion SCI. However, compensatory features of the immune response in AN rats cause delayed tissue death and limit long-term recovery. T cell inhibition combined with other neuroprotective treatment may thus be a promising therapeutic avenue. 2x2 model with 4 groups and 12 total samples. 2 rat strains (athymic nude [AN] and Sprague-Dawley [SD]) and 2 time points (1 week post-injury [acute] and 8 weeks post-injury [chronic]). 3 samples per group, for a total of 12 samples. No technical replicates were performed. Acute SD group = rats 618, 619, and 620. Chronic SD group = rats 605, 606, and 608. Acute AN group = rats 714, 715, and 717. Chronic AN group = rats 707, 712, and 713.

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Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states

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