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Systemic application of IL-4 attenuates secondary local inflammation processes and enhances functional recovery after traumatic spinal cord injury in rats.

ABSTRACT: Background: Traumatic spinal cord injury (SCI) triggers local and systemic inflammation cascades, limiting neuroregeneration and impeding functional recovery. We investigated the systemic effect of immunomodulation with Interleukin-4 (IL-4) on the local immune reaction and regeneration in injured spinal cord tissue, in addition to the systemic cytokine landscape after SCI in rats. Methodology: After performing a T10 laminectomy, 120 female Wistar rats were randomized to either thoracic clip compression/contusion SCI or sham. SCI animals received intraperitoneal (i.p.) IL-4 or vehicle injections twice daily for up to 7 days post-injury (dpi). Rats underwent a battery of neurobehavioral tests and were sacrificed at 1, 3, 7, 14, and 28 dpi. Transcriptomcis, proteomics and immunohistochemistry (IHC) was used to assess macrophage polarization, cellular neurodegeneration, and astrogliosis of explanted spinal cords. High throughput seromics was applied to measure levels of 18 cytokines in rat serum, which were also compared to SCI patient serum data. Results: IL-4-treated rats showed a significantly better recovery in the Basso, Beattie, Bresnahan locomotor rating scale score and several Catwalk XT gait analysis parameters at 14 dpi. RNA-Seq and proteomics analyses revealed a significant upregulation in gene ontologies pertaining to improved axonogenisis and tissue repair along with reduced neuronal death and the pro-inflammatory TNFa signaling. This was verified via IHC, showing a higher abundance of IBA1+/ARG1+ and IBA1+/CD206+ M2-macrophages with a lower abundance of IBA1+/iNOS+ M1-macrophages compared to vehicle-treated rats at 3 dpi. Furthermore, post-traumatic cyst size was significantly reduced with IL-4 treatment at 28 dpi. While APC+ oligodendrocytes showed a significantly higher cell count in the IL-4 group, no significant difference was noted in NeuN+ neurons compared to the vehicle-treated group at 28 dpi. Seromics revealed significantly higher levels of pro-inflammatory serum cytokines in vehicle-treated rats compared to sham rats in the acute to subacute post-injury phase (1, 3 and 7 dpi), which were effectively suppressed by IL-4 treatment. Consistent with our rat model, data analysis of SCI patients revealed improved outcome of patients with low serum levels of pro-inflammatory cytokines reduced by IL-4. Conclusions: Intraperitoneal IL-4 treatment modulated local and systemic inflammation after SCI and improved functional recovery. Transcriptomic and proteomic profiling revealed activation of regenerative and neuroprotective pathways and suppression of pro-inflammatory signaling, supporting the histological and behavioral findings. These results provide mechanistic insight into IL-4’s effects and support its further preclinical evaluation in SCI.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Spinal Cord

SUBMITTER: Marcin Luzarowski

LAB HEAD: Marcin Luzarowski

PROVIDER: PXD065980 | Pride | 2026-03-16

REPOSITORIES: Pride

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			Action	DRS
	EC-24-213-01_20250115154036.raw	Raw
	EC-24-213-02_20250115182305.raw	Raw
	EC-24-213-03_20250115210529.raw	Raw
	EC-24-213-04_20250115234758.raw	Raw
	EC-24-213-05_20250116023020.raw	Raw

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Project description:Abstract Background: Traumatic spinal cord injury (SCI) triggers local and systemic inflammation cascades, limiting neuroregeneration and impeding functional recovery. We investigated the systemic effect of immunomodulation with Interleukin-4 (IL-4) on the local immune reaction and regeneration in injured spinal cord tissue, in addition to the systemic cytokine landscape after SCI in rats. Methodology: After performing a T10 laminectomy, 120 female Wistar rats were randomized to either thoracic clip compression/contusion SCI or sham. SCI animals received intraperitoneal (i.p.) IL-4 or vehicle injections twice daily for up to 7 days post-injury (dpi). Rats underwent a battery of neurobehavioral tests and were sacrificed at 1, 3, 7, 14, and 28 dpi. Transcriptomcis, proteomics and immunohistochemistry (IHC) was used to assess macrophage polarization, cellular neurodegeneration, and astrogliosis of explanted spinal cords. High throughput seromics was applied to measure levels of 18 cytokines in rat serum, which were also compared to SCI patient serum data. Results: IL-4-treated rats showed a significantly better recovery in the Basso, Beattie, Bresnahan locomotor rating scale score and several Catwalk XT gait analysis parameters at 14 dpi. RNA-Seq and proteomics analyses revealed a significant upregulation in gene ontologies pertaining to improved axonogenisis and tissue repair along with reduced neuronal death and the pro-inflammatory TNFa signaling. This was verified via IHC, showing a higher abundance of IBA1+/ARG1+ and IBA1+/CD206+ M2-macrophages with a lower abundance of IBA1+/iNOS+ M1-macrophages compared to vehicle-treated rats at 3 dpi. Furthermore, post-traumatic cyst size was significantly reduced with IL-4 treatment at 28 dpi. While APC+ oligodendrocytes showed a significantly higher cell count in the IL-4 group, no significant difference was noted in NeuN+ neurons compared to the vehicle-treated group at 28 dpi. Seromics revealed significantly higher levels of pro-inflammatory serum cytokines in vehicle-treated rats compared to sham rats in the acute to subacute post-injury phase (1, 3 and 7 dpi), which were effectively suppressed by IL-4 treatment. Consistent with our rat model, data analysis of SCI patients revealed improved outcome of patients with low serum levels of pro-inflammatory cytokines reduced by IL-4. Conclusions: Intraperitoneal IL-4 treatment modulated local and systemic inflammation after SCI and improved functional recovery. Transcriptomic and proteomic profiling revealed activation of regenerative and neuroprotective pathways and suppression of pro-inflammatory signaling, supporting the histological and behavioral findings. These results provide mechanistic insight into IL-4’s effects and support its further preclinical evaluation in SCI.

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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Systemic application of IL-4 attenuates secondary local inflammation processes and enhances functional recovery after traumatic spinal cord injury in rats.

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