Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.
Rawji, Khalil S
Young, Adam MH
Michaels, Nathan J
Kolehmainen, Kathleen L
Kaushik, Deepak K
Keough, Michael B
Knights, Andrew J
Gaffney, Daniel J
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Rawji, K. S., Young, A. M., Ghosh, T., Michaels, N. J., Mirzaei, R., Kappen, J., Kolehmainen, K. L., et al. (2020). Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.. Acta neuropathologica, 139 (5), 893-909. https://doi.org/10.1007/s00401-020-02129-7
Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically-approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate-mapping and multiphoton live imaging show that systemic treatment of 9-12 month old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally-derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.
Microglia, Axons, Macrophages, Animals, Mice, Transgenic, Humans, Multiple Sclerosis, Demyelinating Diseases, Niacin, Rejuvenation, Phagocytosis, Aging, Remyelination
We acknowledge the technical help of Janet Wang, Helvira Melo, and Claudia Silva. We thank Jie Liu for expert help with the lysolecithin injections in Hcar2-/- mice. KSR was supported by a Vanier Canada Graduate Scholarship. NJM and RM were supported by a University of Calgary Eyes High pre- and postdoctoral scholarship, respectively. NJM, MKM, DK and JRP were supported by fellowships from the MS Society of Canada (MSSC); JRP received a Canadian Institutes of Health Research (CIHR) fellowship while KSR also acknowledges T. Chen Fong and a studentship from the MS Society of Canada. W.Tang was supported by a summer studentship from Alberta Innovates Health Solutions. VWY is a Canada Research Chair (Tier 1) in Neuroimmunology. WT holds the BC Leadership Chair in Spinal Cord Research. This work was supported by operating grants from CIHR, MSSC, the AIHS CRIO Team program. This work was also supported by funding from the UK Multiple Sclerosis Society and The Adelson Medical Research Foundation and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (RJMF), and Wellcome grant WT206194 (FC, AJK, DJG). AMHY is in receipt of a Wellcome PhD Fellowship for clinicians. We thank the Hotchkiss Brain Institute AMP Facility for use of the Nikon A1R multiphoton microscope, the Nikon C1si spectral confocal microscope, as well as the ImageXpress Micro Cellular Imaging and Analysis System. We also acknowledge the Live Cell Imaging Facility for providing the Imaris software. Hcar2 null mice were a generous gift from Dr. Stefan Offermanns (Max-Planck Institute, Berlin, Germany).
Wellcome Trust (203151/Z/16/Z)
MRC (via University of Edinburgh) (MR/R015635/1)
Medical Research Council (G0802545)
Medical Research Council (G0300336)
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External DOI: https://doi.org/10.1007/s00401-020-02129-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/301543
Attribution 4.0 International (CC BY)
Licence URL: http://creativecommons.org/licenses/by/4.0/