M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination

Abstract

The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell–derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration.

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Figure 1: A switch from an M1- to an M2-dominant microglia and macrophage response occurs at the initiation of remyelination.
Figure 2: Microglia and peripherally derived macrophages contribute to both M1 and M2 polarized populations during remyelination.
Figure 3: M2 cell conditioned media promotes oligodendrocyte differentiation.
Figure 4: Selective depletion of M1 microglia and macrophages in a demyelinated lesion in the CNS impairs OPC proliferation.
Figure 5: Selective depletion of M2 microglia and macrophages in a demyelinated lesion in the CNS impairs oligodendrocyte differentiation.
Figure 6: Restored remyelination efficiency in aged mice via heterochronic parabiosis is associated with increased densities of M2 polarized cells.
Figure 7: M2 microglia and macrophage densities are increased in acute active and the rim of chronic active multiple sclerosis lesions.
Figure 8: Activin-A is an M2 cell–derived factor that drives oligodendrocyte differentiation during remyelination.

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Acknowledgements

We thank the UK Multiple Sclerosis Tissue Bank for providing human brain tissue, F. Roncaroli (Imperial College London) for neuropathological diagnosis of lesions and R. Nicholas (Imperial College London) for providing clinical history of patients. We also thank W. Mungall, J. Huang, M. Harrisingh, A. Jarjour, M. Bechler, M. Swire, A.-C. Nunes-Fonseca, D. Morrison, and C. Watkins for technical assistance. This work was funded by the UK Multiple Sclerosis Society (R.J.M.F. and C.ff.-C.) and the Wellcome Trust (A.W. and C.ff.-C.), and V.E.M. holds a post-doctoral fellowship from the Multiple Sclerosis Society of Canada.

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V.E.M. conceived the project, designed and carried out the experiments, performed data acquisition, quantification and analysis, and wrote the manuscript. A.B. and A.W. assisted in in vivo studies and A.W. assisted in data interpretation. J.-W.Z. contributed to analysis and quantification of parabiosis lesion tissue. A.B., A.W., T.J.Y. and P.v.W. performed lesioning experiments to provide lesion tissue and assisted in tissue selection. J.M.R., J.L.S., A.J.W. and R.J.M.F. provided parabiosis lesion tissue. R.J.M.F. assisted in study design, data interpretation and manuscript writing. C.ff.-C. supervised the project, assisted in study design, data interpretation, figure preparation and writing of the manuscript.

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Correspondence to Veronique E Miron.

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V.E.M., R.J.M.F. and C.f-C have submitted a patent application pertaining to the use of activin/activin signalling for oligodendrocyte differentiation and/or remyelination.

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Miron, V., Boyd, A., Zhao, J. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16, 1211–1218 (2013). https://doi.org/10.1038/nn.3469

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