Sustained interleukin-10 delivery reduces inflammation and improves motor function after spinal cord injury

Abstract

Background The anti-inflammatory cytokine interleukin-10 (IL-10) has been explored previously as a treatment method for spinal cord injury (SCI) due to its ability to attenuate pro-inflammatory cytokines and reduce apoptosis. Primary limitations when using systemic injections of IL-10 are that it is rapidly cleared from the injury site and that it does not cross the blood–spinal cord barrier. Objective Here, mineral-coated microparticles (MCMs) were used to obtain a local sustained delivery of IL-10 directly into the injury site after SCI. Methods Female Sprague-Dawley rats were contused at T10 and treated with either an intraperitoneal injection of IL-10, an intramedullary injection of IL-10, or MCMs bound with IL-10 (MCMs+IL-10). After treatment, cytokine levels were measured in the spinal cord, functional testing and electrophysiology were performed, axon tracers were injected into the brainstem and motor cortex, macrophage levels were counted using flow cytometry and immunohistochemistry, and lesion size was measured. Results When treated with MCMs+IL-10, IL-10 was significantly elevated in the injury site and inflammatory cytokines were significantly suppressed, prompting significantly less cells expressing antigens characteristic of inflammatory macrophages and significantly more cells expressing antigens characteristic of earlier stage anti-inflammatory macrophages. Significantly more axons were preserved within the rubrospinal and reticulospinal tracts through the injury site when treated with MCMs+IL-10; however, there was no significant difference in corticospinal tract axons preserved, regardless of treatment group. The rats treated with MCMs+IL-10 were the only group with a significantly higher functional score compared to injured controls 28 days post-contusion. Conclusion These data demonstrate that MCMs can effectively deliver biologically active IL-10 for an extended period of time altering macrophage phenotype and aiding in functional recovery after SCI.

Lentiviral interleukin-10 gene therapy preserves fine motor circuitry and function after a cervical spinal cord injury in male and female mice

“…The studies reported here validate that lentiviral IL10 gene therapy via a PLG implant into a left-sided, cervical SCI is associated with significantly improved performance of the left arm, as observed on a ladder beam. A number of groups have reported that IL10 treatment after a thoracic SCI can lead to intraspinal sparing of neurons, axons, and lesion size that is associated with improved locomotor function [23][24][25][26][27][28][29]. We have also previously demonstrated in a left-sided, thoracic SCI that IL10 can shift the inflammatory milieu toward a pro-regenerative phenotype, which was associated with significantly improved locomotor function [37,38] and consistent with the results here in the cervical model.…”

Single-dose mRNA therapy via biomaterial-mediated sequestration of overexpressed proteins

“…Decreased expected time to complete closure with CM-mRNA + MCM treatment in this model indicated that MCMs offer significant increase in potential therapeutic utility of mRNA delivery. As we have previously demonstrated, the promiscuous electrostatic binding of mineral coatings allows for sustained release of a range of other growth factors, cytokines, and enzymes, including bone morphogenetic protein–2 ( 27 , 45 ), vascular endothelial growth factor ( 14 , 27 , 43 ), interleukin-1RA (IL-1RA) ( 41 ), IL-10 ( 46 ), NT-3 (neurotrophin-3) ( 42 ), and chondroitinase ABC ( 47 ). Therefore, our MCM-mediated overexpress and sequester approach may have broad potential in therapeutic applications where in situ production and retention of highly bioactive secreted proteins would be beneficial.…”

Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment

“…GDNF and IL-10 have a potent survival effect on injured neurons after spinal cord injury and reduce secondary damage inflammation and improve motor function 56 – 61 . Previous reports have shown, that cellular GDNF delivery promotes sensory and proriospinal axonal elongation following spinal cord injury and GDNF overexpression by graft hiPSC-derived NPCs increased the differentiation toward a neuronal fate 62 – 65 .…”