Journal
THERANOSTICS
Volume 11, Issue 20, Pages 9805-9820Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.65203
Keywords
interleukin 4; interleukin 13; immune metabolism; polarization; spinal cord injury
Categories
Funding
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2016-79774-R]
- Wings for Life International Foundation
- Red de Terapia Celular (TERCEL)
- la Caixa Foundation [LCF/TR/CI17/10020018, LCF/PR/HA17/52170001]
- NIH [AI 15614]
- Interleukin Foundation
- Fundacion Tatiana Perez de Guzman el Bueno
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The study found that while IL-13 induced anti-inflammatory markers in microglia and macrophages after SCI, it did not promote functional recovery as effectively as IL-4. IL-13 and IL-4 induced different gene signatures in these cells after SCI, with IL-4 shifting metabolism towards oxidative phosphorylation. This metabolic shift is important for minimizing cytotoxic responses of microglia and macrophages.
Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive microglia and macrophages towards an anti-inflammatory phenotype in vitro, here we studied whether administration of IL-13 and IL-4 after SCI leads to beneficial effects. Methods: We injected mice with recombinant IL-13 or IL-4 at 48 h after SCI and assessed their effects on microglia and macrophage phenotype and functional outcomes. We also performed RNA sequencing analysis of macrophages and microglia sorted from the injured spinal cords of mice treated with IL-13 or IL-4 and evaluated the metabolic state of these cells by using Seahorse technology. Results: We observed that IL-13 induced the expression of anti-inflammatory markers in microglia and macrophages after SCI but, in contrast to IL-4, it failed to mediate functional recovery. We found that these two cytokines induced different gene signatures in microglia and macrophages after SCI and that IL-4, in contrast to IL-13, shifted microglia and macrophage metabolism from glycolytic to oxidative phosphorylation. These findings were further confirmed by measuring the metabolic profile of these cells. Importantly, we also revealed that macrophages stimulated with IL-4 or IL-13 are not deleterious to neurons, but they become cytotoxic when oxidative metabolism is blocked. This suggests that the metabolic shift, from glycolysis to oxidative phosphorylation, is required to minimize the cytotoxic responses of microglia and macrophages. Conclusions: These results reveal that the metabolic fitness of microglia and macrophages after SCI contributes to secondary damage and that strategies aimed at boosting oxidative phosphorylation might be a novel approach to minimize the deleterious actions of microglia and macrophages in neurotrauma.
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