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Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions

Abstract

Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6ChiCCR2+ monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6ChiCCR2+ monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

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Figure 1: Brain-specific macrophages (microglia) have an immunomarker profile similar to that of resident blood monocytes.
Figure 2: Normal development, morphology and function of microglia in the absence of CCR2.
Figure 3: Strong reduction of Ly-6ChiCCR2+ monocytes leads to substantially reduced numbers of engrafted microglia in the CNS.
Figure 4: Engraftment of donor-derived GFP+Ly-6ChiCCR2+ monocytes and differentiation into microglia requires a conditioned CNS.
Figure 5: Immigration of Ly-6Chi monocytes into the brain during cuprizone-induced demyelination requires host conditioning.
Figure 6: Adoptively transferred Ly-6ChiCCR2+ monocytes selectively migrate to the demyelinated area in the conditioned CNS.
Figure 7: Selective recruitment of donor-derived Ly-6ChiCCR2+ monocytes after axotomized facial nucleus occurs only in conditioned CNS.

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Acknowledgements

We thank O. Kowatsch, M. Schedensack, E. Pralle, P. Grämmel and S. Blumenau for excellent technical assistance. We thank S. Jung (Rehovot, Israel) for scientific input. This work was supported by grants from Gemeinnützige Hertie-Stiftung to M.P. and D.M., Deutsche Forschungsgemeinschaft (SFB 507 A5 and PR 577) to J.P. and M.P. This project was supported by the DFG research Center for Molecular Physiology of the Brain Göttingen, but support was unfortunately discontinued. M.H. is supported by the Swiss MS Society and the Prof. Dr. Max-Cloëtta Foundation. A.M. and H.S. are fellows of the Gertrud Reemtsma Foundation.

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A.M., H.S., M.N., D.M., U.-K.H., J.P. and M.P. conducted the experiments. M.M., M.H. and W.B. provided reagents and scientific input. A.M., J.P. and M.P. designed the experiments and wrote the manuscript.

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Correspondence to Marco Prinz.

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Mildner, A., Schmidt, H., Nitsche, M. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10, 1544–1553 (2007). https://doi.org/10.1038/nn2015

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