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 (M phi s) and microglia. After SCI, the inflammatory environment is dominated by pro-inflammatory M phi s/microglia, which contribute to secondary cell death and prevent regeneration. Therefore, reprogramming M phi/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 M phi s as carriers to continuously secrete IL-13 (IL-13 M phi s) at the lesion site. Methods M phi s were genetically modified to secrete IL-13 (IL-13 M phi s) and were phenotypically characterized using qPCR, western blot, and ELISA. To analyze the therapeutic potential, the IL-13 M phi s 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 M phi s prestimulated with recombinant IL-13, perilesional transplantation of IL-13 M phi s 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 M phi s resulted in reduced neuronal death and fewer contacts between dystrophic axons and M phi s/microglia, suggesting suppression of axonal dieback. Using IL-4R alpha-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 M phi/microglia responses. Conclusions Collectively, our data suggest that the IL-13-induced anti-inflammatory M phi/microglia phenotype can preserve neuronal tissue and ameliorate axonal dieback, thereby promoting recovery after SCI.