Interleukin-13 immune gene therapy prevents CNS inflammation and demyelination via alternative activation of microglia and macrophages.
Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine interleukin 13 (IL-13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL-13 mediated modulation of cuprizone induced lesions was monitored using T2-weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination. Second, following IL-13 immune gene therapy in cuprizone-treated eGFP+bone marrow chimeric mice, we provide evidence that IL-13 directs the polarization of both brain-resident microglia and infiltrating macrophages towards an alternatively activated phenotype, thereby promoting the conversion of a pro-inflammatory environment toward an anti-inflammatory environment, as further evidenced by gene expression analyses. Finally, we show that IL-13 immune gene therapy is also able to limit lesion severity in a pre-existing inflammatory environment. In conclusion, these results highlight the potential of IL-13 to modulate microglia/macrophage responses and to improve disease outcome in a mouse model for MS. GLIA 2016;64:2181-2200.
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Caroline
C
Guglielmetti
Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Debbie
D
Le Blon
Center for Statistics, I-Biostat, Hasselt University, Hasselt, Belgium.
Eva
E
Santermans
Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Angelica
A
Salas-Perdomo
Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Jasmijn
J
Daans
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.|Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Nathalie
N
De Vocht
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Disha
D
Shah
Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Chloé
C
Hoornaert
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Jelle
J
Praet
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Jurgen
J
Peerlings
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Firat
F
Kara
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Christian
C
Bigot
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.|Icometrix, Leuven, Belgium.
Zhenhua
Z
Mai
Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Herman
H
Goossens
Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.|Center for Statistics, I-Biostat, Hasselt University, Hasselt, Belgium.|Centre for Health Economic Research and Modelling Infectious Diseases (Chermid), University of Antwerp, Antwerp, Belgium.
Niel
N
Hens
Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Sven
S
Hendrix
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Marleen
M
Verhoye
Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Anna M
AM
Planas
Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
Zwi
Z
Berneman
Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Annemie
A
van der Linden
Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. peter.ponsaerts@uantwerpen.be.|Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium. peter.ponsaerts@uantwerpen.be.
Peter
P
Ponsaerts
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016026:Bone Marrow Transplantation; D003471:Cuprizone / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000628:therapy*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D009185:Myelin Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
D000943:Antigens, Differentiation; D016207:Cytokines; D018793:Interleukin-13; D008996:Monoamine Oxidase Inhibitors; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; C485184:enhanced green fluorescent protein; C036763:monocyte-macrophage differentiation antigen; D049452:Green Fluorescent Proteins; D003471:Cuprizone
demyelination; magnetic resonance imaging; multiple sclerosis