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GP130 Regulates Macrophage Polarization and Functional Recovery after Spinal Cord Injury in Rats: A Single-Cell RNA
Mengqi Gao1, Danfen Zhang1, Mingze Liu1
1Neurosurgery Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
Abstract:
Neuroinflammation and macrophage polarization play important roles in secondary injury and functional recovery after spinal cord injury (SCI). GP130, the common signal-transducing receptor subunit of the IL-6 cytokine family, is closely associated with JAK/STAT3-mediated inflammatory signaling. However, its role in macrophage polarization after SCI remains unclear. This study investigated whether GP130 inhibition regulates macrophage polarization and improves functional recovery after SCI. A rat model of T10 spinal cord compression injury was established using a standardized microvascular clip compression method. The GP130 inhibitor SC144 was administered after SCI. Functional recovery was evaluated using BBB scoring and inclined plane tests. Histopathological, ultrastructural, immunofluorescence, flow cytometry, qRT-PCR, western blotting, ELISA, and single-cell RNA sequencing analyses were performed to evaluate tissue injury, inflammatory signaling, and macrophage polarization. Primary bone marrow-derived macrophages were further used to assess the direct effects of GP130 knockdown or pharmacological inhibition on macrophage phenotype in vitro. SCI induced severe locomotor impairment, tissue disruption, ultrastructural damage, and activation of GP130-related inflammatory signaling. SC144 treatment improved functional recovery, reduced inflammatory cytokine expression, and attenuated downstream STAT3 activation. Single-cell RNA sequencing revealed a prominent monocyte/macrophage-related myeloid-cell response after SCI and transcriptional heterogeneity within the myeloid compartment. Immunofluorescence and flow cytometry showed that GP130 inhibition reduced M1-like marker expression and promoted M2-like marker expression in vivo. In primary macrophages, GP130-siRNA and SC144 similarly suppressed M1-like pro-inflammatory marker expression and enhanced M2-like reparative marker expression. GP130 inhibition modulates macrophage polarization and promotes functional recovery after T10 spinal cord compression injury. These findings suggest that GP130-related inflammatory signaling may be a potential therapeutic target for regulating macrophage-mediated neuroinflammation after SCI.
Insights
Inhibiting GP130, a key inflammatory signaling receptor, improves functional recovery after spinal cord injury (SCI) by modulating macrophage polarization. This suggests GP130 as a therapeutic target for neuroinflammation in SCI.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Neuroinflammation and macrophage polarization are critical in spinal cord injury (SCI) secondary damage and recovery.
- GP130, a receptor subunit in the IL-6 cytokine family, links to JAK/STAT3 inflammatory pathways, but its role in SCI macrophage polarization is unknown.
Purpose of the Study:
- To investigate if GP130 inhibition influences macrophage polarization and enhances functional recovery post-SCI.
- To explore GP130's role in the inflammatory and cellular responses following spinal cord injury.
Main Methods:
- A rat T10 spinal cord compression injury model was used, with GP130 inhibitor SC144 administered post-injury.
- Functional recovery assessed via BBB scores and inclined plane tests.
- Analyses included histopathology, ultrastructural examination, immunofluorescence, flow cytometry, qRT-PCR, Western blotting, ELISA, and single-cell RNA sequencing.
Main Results:
- SCI caused significant locomotor deficits, tissue damage, and activated GP130 signaling.
- SC144 treatment improved functional recovery, reduced inflammatory cytokines, and decreased STAT3 activation.
- GP130 inhibition shifted macrophages from M1 (pro-inflammatory) to M2 (reparative) phenotypes in vivo and in vitro.
Conclusions:
- GP130 inhibition modulates macrophage polarization, promoting M2 phenotypes and improving functional outcomes after SCI.
- Targeting GP130-mediated inflammatory signaling presents a potential therapeutic strategy for SCI neuroinflammation and recovery.
