Macrophage-based delivery of interleukin-13 improves functional and histopathological outcomes following spinal cord injury

Abstract

Background Spinal cord injury (SCI) elicits a robust neuroinflammatory reaction which, in turn, exacerbates the initial mechanical damage. Pivotal players orchestrating this response are macrophages (Mφs) and microglia. After SCI, the inflammatory environment is dominated by pro-inflammatory Mφs/microglia, which contribute to secondary cell death and prevent regeneration. Therefore, reprogramming Mφ/microglia towards a more anti-inflammatory and potentially neuroprotective phenotype has gained substantial therapeutic interest in recent years. Interleukin-13 (IL-13) is a potent inducer of such an anti-inflammatory phenotype. In this study, we used genetically modified Mφs as carriers to continuously secrete IL-13 (IL-13 Mφs) at the lesion site. Methods Mφs were genetically modified to secrete IL-13 (IL-13 Mφs) and were phenotypically characterized using qPCR, western blot, and ELISA. To analyze the therapeutic potential, the IL-13 Mφs were intraspinally injected at the perilesional area after hemisection SCI in female mice. Functional recovery and histopathological improvements were evaluated using the Basso Mouse Scale score and immunohistochemistry. Neuroprotective effects of IL-13 were investigated using different cell viability assays in murine and human neuroblastoma cell lines, human neurospheroids, as well as murine organotypic brain slice cultures. Results In contrast to Mφs prestimulated with recombinant IL-13, perilesional transplantation of IL-13 Mφs promoted functional recovery following SCI in mice. This improvement was accompanied by reduced lesion size and demyelinated area. The local anti-inflammatory shift induced by IL-13 Mφs resulted in reduced neuronal death and fewer contacts between dystrophic axons and Mφs/microglia, suggesting suppression of axonal dieback. Using IL-4Rα-deficient mice, we show that IL-13 signaling is required for these beneficial effects. Whereas direct neuroprotective effects of IL-13 on murine and human neuroblastoma cell lines or human neurospheroid cultures were absent, IL-13 rescued murine organotypic brain slices from cell death, probably by indirectly modulating the Mφ/microglia responses. Conclusions Collectively, our data suggest that the IL-13-induced anti-inflammatory Mφ/microglia phenotype can preserve neuronal tissue and ameliorate axonal dieback, thereby promoting recovery after SCI.

Pro-Inflammatory Biomarkers and Long Term Neurological Outcomes in Hypothermia Plus Melatonin Treated Newborns. A Pilot Clinical Trial

“…In addition, longterm neurodevelopment improves directly correlates to the serum decrease maintained over time. The role of IL-13 in brain damage is still unclear and the interpretation of its plasma levels is controversial, since recent animal experimentation attributes to this cytokine: anti-inflammatory and neuroprotective effects [53,54], reactivation of neuronal pyroptosis and increased neurological deficits in models of cerebral hemorrhage [55,56]. In a recent clinical trial in asphyxiated human neonates, Massaro et al observed that an early plasma increase (24 hours) of cytokines such as IL-1 and IL-13 was related to greater brain injury as seen on magnetic resonance imaging.…”

Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition

“…A standardized T-cut spinal cord hemisection injury was performed as previously described [18–20]. In brief, mice were anesthetized with 2-3% isoflurane and a partial laminectomy was performed at thoracic level 8.…”

“…Inhibition of PDE4B suppresses the neuroinflammatory responses of macrophages and microglia, while PDE4D blockage has been shown to successfully boost myelin regeneration and enhance neuroplasticity [13][14][15][16]. Targeting these individual subtypes circumvented the emetic side-effects accompanied by pan PDE4 inhibitors such as roflumilast and rolipram, and is predicted a valuable strategy to target neuroinflammation [17].…”

Oxidative DNA Damage in the Pathophysiology of Spinal Cord Injury: Seems Obvious, but Where Is the Evidence?

“…These procedures are followed by physical therapy to improve independence in daily living and reintegration into society [ 86 ]. Besides the general clinically approved therapies ( Figure 4 ), new state-of-the-art treatments are being developed to stimulate neuroprotection and neuroregeneration or improve function using neuroprosthetics or neurostimulation [ 87 , 88 , 89 , 90 ]. Despite these continued efforts to find an effective treatment, current strategies do not cure SCI and induce limited functional recovery, highlighting the need for alternative and complementary approaches to treat SCI patients.…”