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Lentiviral-mediated administration of IL-25 in the CNS induces alternative activation of microglia

Gene Therapy volume 20, pages 487–496 (2013)Cite this article

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Abstract

Interleukin-25 (IL-25) is the only anti-inflammatory cytokine of the IL-17 family, and it has been shown to be efficacious in inhibiting neuroinflammation. Known for its effects on cells of the adaptive immune system, it has been more recently described to be effective also on cells of the innate immune system, namely macrophages. We used a lentiviral-mediated gene therapy approach to deliver IL-25 to the central nervous system (CNS) in two mouse models of neuroinflammation, entorhinal cortex lesion and experimental autoimmune encephalomyelitis. In both, we found that IL-25 gene therapy was able to modulate CNS myeloid cells, either infiltrating macrophages or resident microglia, towards an anti-inflammatory, tissue-protective phenotype, as testified by the increase in markers such as Arginase-1 (Arg1), Mannose receptor 1 (CD206) and Chitinase 3-like 3 (Ym1). As a consequence, neuroinflammation was partly inhibited and the CNS protected from immune-mediated damage. To our knowledge, this is the first example of M2 shift (alternative activation) induced in vivo on CNS-resident myeloid cells by gene therapy, and may constitute a promising strategy to investigate the potential role of protective microglia in neurological disorders.

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Acknowledgements

We are grateful to P Brown for helpful discussion; to Prof. L Naldini for providing the lentiviral backbone; to A Gatta, E Butti, D Dræby, M Rytz Hansen and P Nyborg Nielsen for technical help.

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Authors and Affiliations

  1. Division of Neuroscience, Clinical Neuroimmunology Unit, Institute of Experimental Neurology-INSpe, San Raffaele Scientific Institute, Milan, Italy

    C Maiorino, F Ruffini, A Bergami, L Garzetti & R Furlan

  2. Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    R Khorooshi, M Løbner & T Owens

  3. Division of Neuroscience, Neuroimmunology Unit, Institute of Experimental Neurology–INSpe, San Raffaele Scientific Institute, Milan, Italy

    G Martino

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  1. C Maiorino
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  2. R Khorooshi
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  3. F Ruffini
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  5. A Bergami
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Correspondence to R Furlan.

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The authors declare no conflict of interest.

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This work has been supported by FISM (RF), Danish Agency for Science, Technology and Innovation (TO), Lundbeck Foundation (ML) and MSIF Du Pré Grant Fellow (CM). CM conducted this study as partial fulfillment of her PhD in Molecular Medicine, Program in Experimental Neurology, San Raffaele University, Milan, Italy.

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Maiorino, C., Khorooshi, R., Ruffini, F. et al. Lentiviral-mediated administration of IL-25 in the CNS induces alternative activation of microglia. Gene Ther 20, 487–496 (2013). https://doi.org/10.1038/gt.2012.58

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