Systemic Interleukin-4 Administration after Spinal Cord Injury Modulates Inflammation and Promotes Neuroprotection

Abstract

Traumatic spinal cord injury (SCI) causes dramatic disability and dysfunction in the motor, sensory and autonomic systems. The severe inflammatory reaction that occurs after SCI is strongly associated with further tissue damage. As such, immunomodulatory strategies have been developed, aimed at reducing inflammation, but also at shaping the immune response in order to protect, repair and promote regeneration of spared neural tissue. One of those promising strategies is the intraspinal administration of the cytokine interleukin-4 (IL-4) that was shown to promote a phenotype on specific immune cells associated with neuroprotection and repair. In this work, we evaluated if a systemic delivery of IL-4 for a 7-days period was also capable of promoting neuroprotection after SCI by analyzing different neural cells populations and motor recovery. IL-4 treatment promoted an elevation of the anti-inflammatory cytokine IL-10 in the serum both at 24 h and 7 days after injury. Locally, treatment with IL-4 led to a reduction on cells expressing markers associated with inflammation, CD11b/c and iNOS. Importantly, IL-4 treatment increased the neuronal markers βIII-tubulin and NeuN, and the oligodendrocyte marker O4, suggesting a neuroprotective effect. Moreover, 100% of the animals treated with IL-4 were able to recover weight support against only 33% of saline treated animals. Overall, these results show that systemic administration of IL-4 positively impacts different aspects of spinal cord injury, creating a more favorable environment for recovery to take place.

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

“…More direct evidence comes from efficacy associated with the application of cytokines, specifically IL-4, that drive M2 macrophage activation in vitro [166]. Either systemic or intraspinal administration of IL-4 after SCI increases production of the anti-inflammatory cytokine, IL-10, coincident with increases in markers associated with M2 macrophage activation [167,168]. IL-4 administration also reduces iNOS, a purported mediator of M1 neurotoxicity, regardless of administration route [167,168].…”

“…Either systemic or intraspinal administration of IL-4 after SCI increases production of the anti-inflammatory cytokine, IL-10, coincident with increases in markers associated with M2 macrophage activation [167,168]. IL-4 administration also reduces iNOS, a purported mediator of M1 neurotoxicity, regardless of administration route [167,168]. In addition, IL-4 treatment facilitates neuroprotection as indicated by increased tissue sparing and functional recovery [167,168].…”

Modulation of inflammatory factors predicts the outcome following spinal cord injury

“…The pro-inflammatory cytokines such as MHC-I and nitric oxide (NO), all contribute to inflammation and tissue damage [26]. By contrast, the pro-regenerative cytokines including interleukin (IL)-4, IL-10 contribute to wound healing and tissue repair, and enhance regrowth of axons [27]. However, few studies have explored their roles in assessing SCI severity in rats with spine trauma.…”

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

“…like macrophage phenotypes after stroke (52,53), spinal cord injury (SCI) (54)(55)(56), and peripheral nerve injury (PNI) (17,57) at doses ranging from 250-500 ng. IL-4 stimulates astrocytes to secrete growth factors, and promotes microglia to express M2 phenotypic markers as well (58).…”

“…As mentioned, IL-4 alone has been delivered after stroke, SCI, and PNI. This method may have rescued functional deficits in IL-4 knockout mice suffering stroke (52) and reports in SCI are conflicting (56,69). This ambiguity could be because recombinant protein delivery has yet to fully address the challenges of short half-lives (70,71), suboptimal efficacy (72), and immunogenicity (73,74).…”