Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury
Amo Aparicio, Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)
Garcia Garcia, Joana (Universitat Autònoma de Barcelona. Institut de Neurociències)
Francos Quijorna, Isaac (King's College London. Wolfson Centre for Age-Related Diseases)
Urpi, Andrea (Universitat Autònoma de Barcelona. Institut de Neurociències)
Esteve-Codina, Anna (Universitat Pompeu Fabra)
Gut, Marta (Universitat Pompeu Fabra)
Quintana Romero, Albert (Universitat Autònoma de Barcelona. Institut de Neurociències)
Lopez-Vales, Ruben (Universitat Autònoma de Barcelona. Institut de Neurociències)

Data:	2021
Resum:	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.
Ajuts:	Ministerio de Economía, Industria y Competitividad SAF2016-79774-R
Nota:	Altres ajuts: Wings for Life International Foundation; Red de Terapia Celular (TERCEL); La Caixa Foundation (LCF/TR); NIH Grant AI 15614; Interleukin Foundation;mFundación Tatiana Pérez de Guzmán el Bueno/CI17/10020018 i LCF/PR/HA17/
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Interleukin 4 ; Interleukin 13 ; Immune metabolism ; Polarization ; Spinal cord injury
Publicat a:	Theranostics, Vol. 11 Num. 20 (october 2021) , p. 9805-9820, ISSN 1838-7640

DOI: 10.7150/thno.65203
PMID: 34815787

16 p, 1.9 MB

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