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The active contribution of OPCs to neuroinflammation is mediated by LRP1

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Abstract

Oligodendrocyte progenitor cells (OPCs) account for about 5% of total brain and spinal cord cells, giving rise to myelinating oligodendrocytes that provide electrical insulation to neurons of the CNS. OPCs have also recently been shown to regulate inflammatory responses and glial scar formation, suggesting functions that extend beyond myelination. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifaceted phagocytic receptor that is highly expressed in several CNS cell types, including OPCs. Here, we have generated an oligodendroglia-specific knockout of LRP1, which presents with normal myelin development, but is associated with better outcomes in two animal models of demyelination (EAE and cuprizone). At a mechanistic level, LRP1 did not directly affect OPC differentiation into mature oligodendrocytes. Instead, animals lacking LRP1 in OPCs in the demyelinating CNS were characterized by a robust dampening of inflammation. In particular, LRP1-deficient OPCs presented with impaired antigen cross-presentation machinery, suggesting a failure to propagate the inflammatory response and thus promoting faster myelin repair and neuroprotection. Our study places OPCs as major regulators of neuroinflammation in an LRP1-dependent fashion.

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Acknowledgements

We thank Dr. Sanja Arandjelovic, Courtney Rivet-Noor and Andrea R. Merchak (University of Virginia) for critical reading of the manuscript. We thank Dr. Ioana A. Marin (Stanford) for insightful scientific discussions. Dr. Timothy Bullock (University of Virginia) generously provided OT-I mice for this study. The authors are supported by grants from the NINDS R01 NS083542 and R21 NS111204, the National Multiple Sclerosis Society PP1978, the Double Hoo Research Grant, and the Owens family foundation. A.F.C. is supported by T32 GM008328. D.R. is supported by T32 GM007055. S.M.S. is supported by T32 GM007267 and F31 NS103327.

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  1. Department of Neuroscience, Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA

    Anthony Fernández-Castañeda, Megan S. Chappell, Dorian A Rosen, Scott M. Seki, Rebecca M. Beiter, David M. Johanson, Delaney Liskey, Christopher C. Overall & Alban Gaultier

  2. Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA

    Anthony Fernández-Castañeda, Scott M. Seki & Rebecca M. Beiter

  3. Graduate Program in Pharmacological Sciences, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA

    Dorian A Rosen

  4. Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA

    Scott M. Seki

  5. Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA

    Emily Farber & Suna Onengut-Gumuscu

  6. Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Jeffrey L. Dupree

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  1. Anthony Fernández-Castañeda
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Fernández-Castañeda, A., Chappell, M.S., Rosen, D.A. et al. The active contribution of OPCs to neuroinflammation is mediated by LRP1. Acta Neuropathol 139, 365–382 (2020). https://doi.org/10.1007/s00401-019-02073-1

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