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

Journal of Neuroinflammation, 2025 · DOI: https://doi.org/10.1186/s12974-025-03379-6 · Published: February 14, 2025

Simple Explanation

Rehabilitative training after spinal cord injury (SCI) is less effective in the chronic stage. SCI-induced inflammation, elevated in the subacute period, may play a role. Injecting lipopolysaccharide (LPS) alongside training improves recovery in chronic SCI, suggesting LPS could reopen a window of plasticity late after injury. Microglia react to LPS and are implicated in facilitating recovery following SCI. The study examines microglial responses in subacute and chronic SCI with and without an LPS injection using single-cell RNA sequencing to understand how microglia change in response to LPS following SCI to promote neuroplasticity. Microglial states following an inflammatory stimulus in chronic injury incompletely recapitulate the subacute injury environment. The study contributes to an understanding of how microglia and LPS-induced neuroinflammation contribute to plasticity following SCI.

Study Duration

Not specified

Participants

20 adult female Lewis rats for single-cell RNA sequencing, 24 for immunofluorescence staining

Evidence Level

Level 3: Single-cell RNA sequencing and Immunofluorescence study

Key Findings

1
Subacute SCI is characterized by a disease-associated microglial (DAM) signature, while chronic SCI is highly heterogeneous, with both injury-induced and homeostatic states.
2
DAM states exhibit predicted metabolic pathway activity and neuronal interactions that are associated with potential mediators of plasticity.
3
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.

Research Summary

This study investigates the microglial response from subacute to chronic cervical SCI in rats, finding distinct microglial signatures that overlap between the subacute and chronic periods. The subacute period is characterized by a shift away from homeostatic microglial states and the establishment of a range of injury-induced states, predominantly proliferative and DAM states. Chronic SCI retains an injury-induced signature, including IRM, MHC-II- and Ccl3/4-expressing microglia, but at decreased levels, with more microglia expressing a homeostatic signature. LPS injection in chronic injury induces a primed microglial state associated with elevated translation-related genes. LPS injection boosts DAM in degenerated tracts caudal to the injury site, which may enable improved debris clearance and improve the microenvironment for axon growth, demonstrating that a diverse microglia response is initiated by SCI and persists chronically, with multiple mechanisms to boost plasticity.

Practical Implications

Therapeutic target identification

Microglia and DAM states could be targeted to enhance plasticity and recovery after SCI.

Optimizing rehabilitation strategies

Timing and combination of rehabilitation with inflammatory stimuli like LPS should be carefully considered to maximize benefits.

Understanding chronic SCI

The persistence of injury-induced microglial states in chronic SCI suggests ongoing inflammatory processes that could be modulated to improve long-term outcomes.

Study Limitations

1
The study does not show causative gain-of-function or loss-of-function roles of microglial states.
2
Limited in showing causative gain-of- function or loss-of-function roles of these microglial states
3
Further work is necessary to understand how these changes contribute to the complex injury microenvironment

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