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Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Abstract

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.

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Acknowledgements

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) (Grant No. 690720) 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 and 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).

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SupplementaryFigure1Therearenostatisticallysignificantdifferencesinlesionepicenterareabetweenyoungandmiddle-agemice. Lesion epicenter areas were quantified using the myelin stain, eriochrome cyanine, at Days 3, 7, and 21 post-lysolecithin. No differences were detected between young and middle-age mice at any time point. Values are represented as mean with the standard error of the mean. Between 5 and 7 mice were analyzed per age group for each time point and results were analyzed with a 2-way ANOVA with a Bonferroni’s post hoc test. SupplementaryFigure2Niacinisanovelstimulatorofyoungandmiddle-agedmacrophagesandactsthroughtheniacinreceptor,GPR109A(Hcar2).ah. The elevation of several cytokines/chemokines induced by niacin (100 μM) and LPS (100 ng/mL), beyond LPS alone, is lost in Hcar2-/- BMDM. i,j. Niacin (100 μM) has no effect on the expression of Cd68(i) or Mertk(j) in both wildtype and Hcar2-/- BMDM. For panels a – h, values are represented as mean with the standard error of the mean of quadruplicate cultures. For panels i – j, values are represented as mean with the standard error of the mean pooled from two independent experiments of triplicate cultures each. For panels a – h, results were analyzed by 1-way ANOVA with Dunnett post hoc test relative to the LPS group. For panels i – j, results were normalized to the respective control mean value and then analyzed by 2-way ANOVA with Bonferroni post hoc test. * p < 0.05; ** p < 0.01; *** p < 0.001 (a-h: compared to LPS; i-j: relative to wildtype). SupplementaryFigure3ThereisnodifferenceinOPCrecruitmentorremyelinationbetweenwildtypeandHcar2-/-mice.a. Lesions from wildtype and Hcar2-/- mice do not have any difference in Olig2+ PDGFRα+ OPC recruitment 10 days post-demyelination. b. There is no difference in the area of MBP within the lesion between wildtype and Hcar2-/- mice 10 days post-demyelination. Values are represented as mean with the standard error of the mean. Results were analyzed with a 2-tailed student’s t test (n.s. = not significant). Each data point represents 1 mouse. SupplementaryFigure4Treatmentwithniacindoesnotenhancemacrophage/microgliamotility.a. Representative diagram displaying displacement vectors (blue) of individual macrophages/microglia over exvivo multiphoton live imaging session in vehicle- and niacin-treated lesions 3 days post-demyelination. Thy1YFP+ axons are shown in white. b. Lesions from vehicle-treated and niacin-treated mice have no difference in the amount of Cx3cr1GFP/+ macrophages/microglia in the lesions at 3 days post-demyelination. c,d. Graphs showing no difference in the mean displacement (c) or track straightness (d) of individual macrophages/microglia in lesions from vehicle-treated and niacin-treated mice 3 days post-demyelination. Values are represented as mean with the standard error of the mean. Results were analyzed with a 2-tail student’s t test (n.s. = not significant). For panel b, each data point represents 1 mouse. For panels c and d, between 11 and 56 cells were quantified per mouse from 3 vehicle-treated mice and 3 niacin-treated mice. Scale bar equals 20 μm. SupplementaryFigure5Treatmentwithniacindoesnotalterbloodmonocyteprofileafter3or7daysoftreatment. Representative flow cytometry plots of blood monocytes isolated from demyelinated mice (a: Day 3; c: Day 7) treated with either saline vehicle or niacin 100 mg/kg IP once a day from Day 1 to Day 3 (a) or to Day 7 (c). There are no differences in the percentages of CD45+ CD11b+ CD115+ circulating monocytes, CD45+ CD11b+ CD115+ Ly6CHi pro-inflammatory monocytes, CD45+ CD11b+ CD115+ Ly6CInt monocytes, or CD45+ CD11b+ CD115+ Ly6CLo patrolling monocytes between vehicle- and niacin-treated mice (b: Day 3; d: Day 7). In addition, there is no difference in the mean fluorescence intensity of Ly6C on circulating monocytes between vehicle- and niacin-treated mice. Values are represented as mean with the standard error of the mean. Results were analyzed with a 1-tail student’s t test (n.s. = not significant). Each data point represents 1 mouse. SupplementaryFigure6Treatmentwithniacindoesnotaltermacrophage/microgliadensityafter3or7daysoftreatment.a. Representative images depicting lesions immunostained for Iba1 at 3 and 7 days post-demyelination from middle-aged demyelinated mice receiving either saline vehicle or niacin once a day for 3 or 7 days at a dose of 100 mg/kg IP, with quantitation in b.c. Representative images of lysolecithin lesions from middle-aged CX3CR1CreER :Rosa26TdT Ai9 mice treated with either vehicle or niacin once a day for 7 days stained with an antibody against Iba1 (green). d. The number of microglia (Ai9+/Iba1+) within the lesion does not differ between vehicle- and niacin-treated mice on Day 7 post-lysolecithin. Values are represented as mean with the standard error of the mean. For panel b, between 6 and 8mice were analyzed per treatment group for each time point and results were analyzed with a 2-way ANOVA with a Bonferroni’s post hoc test. For panel d, results were analyzed with a 2-tail student’s t test (n.s. = not significant). Scale bars equal 100 μm. SupplementaryFigure7TreatmentwithniacindoesnotaltertheprocessoutgrowthoradherenceofOPCsinculture.a. Representative images of OPCs stained for the sulfatide O4 (green) and Hoechst (blue). b,c. Quantification of process outgrowth (b) and number of cells (c), showing no difference between control- and niacin-treated OPCs. Values are represented as mean with the standard error of the mean. Results were analyzed with a 2-tail student’s t test (n.s. = not significant). Scale bar equals 200 μm. SupplementaryFigure8Thereisnodifferenceinaxonaldensitybetweenlesionsfrommiddle-agedmicetreatedwitheithervehicleorniacin. Quantification of axonal density from electron micrographs of lesion cores from 3 vehicle- and 3 niacin-treated mice at 21 days post-demyelination. Values are represented as mean with the standard error of the mean. Results were analyzed with a 1-tail student’s t test. Each data point represents 1 mouse (n.s. = not significant). SupplementaryFigure9TreatmentwithniacindoesnotalterexpressionofIL-1βwithinlesionsfrommiddle-agedmice.a. Representative images depicting lesions immunostained for CD45 (white) and IL-1β (red) at 3 days post-demyelination from middle-aged demyelinated mice receiving either saline vehicle or niacin once a day for 3 days at a dose of 100 mg/kg IP. b. There is no difference in the percentage of IL-1β associated with CD45+ cells in lesions from both groups. c. Normalized mean fluorescence intensity (MFI) of IL-1β between lesions from vehicle- and niacin-treated mice 3 days post-demyelination did not differ. Values are represented as mean with the standard error of the mean. Results were analyzed with a 1-tail student’s t-test and each data point represents 1 mouse (n.s. = not significant). Scale bar equals 100 μm. SupplementaryFigure10Treatmentwithniacindoesnotalterexpressionofgenesinvolvedinreversecholesteroltransport.a,b,c. Niacin alone (100 µM) has no effect on the expression of Abca1(a), Abcg1(b), and Apoe(c) in both wildtype and Hcar2-/- BMDM. Values are represented as mean with the standard error pooled from two independent experiments, of triplicate cultures each. Results were normalized to the respective control mean value and then analyzed by 2-way ANOVA with Bonferroni post hoc test (PDF 15875 kb)

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Rawji, K.S., Young, A., Ghosh, T. et al. Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system. Acta Neuropathol (2020). https://doi.org/10.1007/s00401-020-02129-7

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Keywords

  • Remyelination
  • Microglia
  • Macrophages
  • Aging
  • Oligodendrocyte progenitor cells
  • Phagocytosis