TY - JOUR
T1 - Interleukin-13 immune gene therapy prevents CNS inflammation and demyelination via alternative activation of microglia and macrophages
AU - Guglielmetti, Caroline
AU - Le Blon, Debbie
AU - Santermans, Eva
AU - Salas-Perdomo, Angelica
AU - Daans, Jasmijn
AU - De Vocht, Nathalie
AU - Shah, Disha
AU - Hoornaert, Chloé
AU - Praet, Jelle
AU - Peerlings, Jurgen
AU - Kara, Firat
AU - Bigot, Christian
AU - Mai, Zhenhua
AU - Goossens, Herman
AU - Hens, Niel
AU - Hendrix, Sven
AU - Verhoye, Marleen
AU - Planas, Anna M.
AU - Berneman, Zwi
AU - van der Linden, Annemie
AU - Ponsaerts, Peter
N1 - Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - demyelination
KW - magnetic resonance imaging
KW - multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=84989333166&partnerID=8YFLogxK
U2 - 10.1002/glia.23053
DO - 10.1002/glia.23053
M3 - Article
C2 - 27685637
AN - SCOPUS:84989333166
SN - 0894-1491
VL - 64
SP - 2181
EP - 2200
JO - Glia
JF - Glia
IS - 12
ER -