The active contribution of OPCs to neuroinflammation is mediated by LRP1

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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References

  1. 1.

    Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149. https://doi.org/10.1038/nn.2887

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S et al (2004) bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 306:2111–2115. https://doi.org/10.1126/science.1103709

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Auderset L, Cullen CL, Young KM (2016) Low density lipoprotein-receptor related protein 1 is differentially expressed by neuronal and glial populations in the developing and mature mouse central nervous system. PLoS ONE 11:e0155878. https://doi.org/10.1371/journal.pone.0155878

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J et al (2005) Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 11:966–972. https://doi.org/10.1038/nm1279

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    CAS  Article  Google Scholar 

  6. 6.

    Behjati S, Frank MH (2009) The effects of tamoxifen on immunity. Curr Med Chem 16:3076–3080

    CAS  Article  Google Scholar 

  7. 7.

    Binder RJ, Han DK, Srivastava PK (2000) CD91: a receptor for heat shock protein gp96. Nat Immunol 1:151–155. https://doi.org/10.1038/77835

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Binder RJ, Srivastava PK (2004) Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA 101:6128–6133. https://doi.org/10.1073/pnas.0308180101

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Brifault C, Gilder AS, Laudati E, Banki M, Gonias SL (2017) Shedding of membrane-associated LDL receptor-related protein-1 from microglia amplifies and sustains neuroinflammation. J Biol Chem 292:18699–18712. https://doi.org/10.1074/jbc.M117.798413

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N et al (2006) Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 116:905–915. https://doi.org/10.1172/JCI26836

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Butti E, Bacigaluppi M, Chaabane L, Ruffini F, Brambilla E, Berera G et al (2019) Neural stem cells of the subventricular zone contribute to neuroprotection of the corpus callosum after cuprizone-induced demyelination. J Neurosci 39:5481–5492. https://doi.org/10.1523/JNEUROSCI.0227-18.2019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M, Sen P et al (2018) Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359:684–688. https://doi.org/10.1126/science.aan4183

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173. https://doi.org/10.1056/NEJMoa010994

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Chew LJ, King WC, Kennedy A, Gallo V (2005) Interferon-gamma inhibits cell cycle exit in differentiating oligodendrocyte progenitor cells. Glia 52:127–143. https://doi.org/10.1002/glia.20232

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chuang TY, Guo Y, Seki SM, Rosen AM, Johanson DM, Mandell JW et al (2016) LRP1 expression in microglia is protective during CNS autoimmunity. Acta Neuropathol Commun 4:68. https://doi.org/10.1186/s40478-016-0343-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Dai J, Bercury KK, Ahrendsen JT, Macklin WB (2015) Olig1 function is required for oligodendrocyte differentiation in the mouse brain. J Neurosci 35:4386–4402. https://doi.org/10.1523/JNEUROSCI.4962-14.2015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Denker SP, Ji S, Dingman A, Lee SY, Derugin N, Wendland MF et al (2007) Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem 100:893–904. https://doi.org/10.1111/j.1471-4159.2006.04162.x

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Emery B, Dugas JC (2013) Purification of oligodendrocyte lineage cells from mouse cortices by immunopanning. Cold Spring Harb Protoc 2013:854–868. https://doi.org/10.1101/pdb.prot073973

    Article  PubMed  Google Scholar 

  19. 19.

    Falcao AM, van Bruggen D, Marques S, Meijer M, Jakel S, Agirre Floriddia E et al (2018) Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat Med 24:1837–1844. https://doi.org/10.1038/s41591-018-0236-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fernandez-Castaneda A, Arandjelovic S, Stiles TL, Schlobach RK, Mowen KA, Gonias SL et al (2013) Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris. J Biol Chem 288:4538–4548. https://doi.org/10.1074/jbc.M112.384693

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Fernandez-Castaneda A, Gaultier A (2016) Adult oligodendrocyte progenitor cells—multifaceted regulators of the CNS in health and disease. Brain Behav Immun 57:1–7. https://doi.org/10.1016/j.bbi.2016.01.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ford ML, Evavold BD (2005) Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol 35:76–85. https://doi.org/10.1002/eji.200425660

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705–714. https://doi.org/10.1038/nrn917

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Gaultier A, Arandjelovic S, Niessen S, Overton CD, Linton MF, Fazio S et al (2008) Regulation of tumor necrosis factor receptor-1 and the IKK-NF-kappaB pathway by LDL receptor-related protein explains the antiinflammatory activity of this receptor. Blood 111:5316–5325. https://doi.org/10.1182/blood-2007-12-127613

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gaultier A, Hollister M, Reynolds I, Hsieh EH, Gonias SL (2010) LRP1 regulates remodeling of the extracellular matrix by fibroblasts. Matrix Biol 29:22–30. https://doi.org/10.1016/j.matbio.2009.08.003

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Gaultier A, Wu X, Le Moan N, Takimoto S, Mukandala G, Akassoglou K et al (2009) Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis. J Cell Sci 122:1155–1162. https://doi.org/10.1242/jcs.040717

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Goldberg J, Daniel M, van Heuvel Y, Victor M, Beyer C, Clarner T et al (2013) Short-term cuprizone feeding induces selective amino acid deprivation with concomitant activation of an integrated stress response in oligodendrocytes. Cell Mol Neurobiol 33:1087–1098. https://doi.org/10.1007/s10571-013-9975-y

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Goldmann T, Wieghofer P, Muller PF, Wolf Y, Varol D, Yona S et al (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16:1618–1626. https://doi.org/10.1038/nn.3531

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB et al (2003) A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425:917–925. https://doi.org/10.1038/nature02033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Gonias SL, Campana WM (2014) LDL receptor-related protein-1: a regulator of inflammation in atherosclerosis, cancer, and injury to the nervous system. Am J Pathol 184:18–27. https://doi.org/10.1016/j.ajpath.2013.08.029

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gonzalez GA, Hofer MP, Syed YA, Amaral AI, Rundle J, Rahman S et al (2016) Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system. Sci Rep 6:31599. https://doi.org/10.1038/srep31599

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Hart JP, Gunn MD, Pizzo SV (2004) A CD91-positive subset of CD11c+ blood dendritic cells: characterization of the APC that functions to enhance adaptive immune responses against CD91-targeted antigens. J Immunol 172:70–78

    CAS  Article  Google Scholar 

  33. 33.

    Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS (1991) 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem 266:21232–21238

    CAS  PubMed  Google Scholar 

  34. 34.

    Hughes EG, Kang SH, Fukaya M, Bergles DE (2013) Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci 16:668–676. https://doi.org/10.1038/nn.3390

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J (2001) A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med 194:669–676. https://doi.org/10.1084/jem.194.5.669

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477. https://doi.org/10.1093/brain/awn080

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J et al (2013) Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci 16:1401–1408. https://doi.org/10.1038/nn.3505

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118:723–736. https://doi.org/10.1007/s00401-009-0591-3

    Article  PubMed  Google Scholar 

  39. 39.

    Kirby LA, Jin J, Gonzalez-Cardona J, Smith M, Martin K, Wang J et al (2019) Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nature commun 10:3887. https://doi.org/10.1038/s41467-019-11638-3

  40. 40.

    Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332. https://doi.org/10.1523/JNEUROSCI.2615-05.2006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Bruck W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131:1749–1758. https://doi.org/10.1093/brain/awn096

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Doring A, Sloka S et al (2012) Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol 72:419–432. https://doi.org/10.1002/ana.23599

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008) LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev 88:887–918

    CAS  Article  Google Scholar 

  44. 44.

    Lin JP, Mironova YA, Shrager P, Giger RJ (2017) LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair. eLife. https://doi.org/10.7554/eLife.30498

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Lin W, Kemper A, Dupree JL, Harding HP, Ron D, Popko B (2006) Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain 129:1306–1318. https://doi.org/10.1093/brain/awl044

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD et al (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109:75–86

    CAS  Article  Google Scholar 

  47. 47.

    Mantuano E, Brifault C, Lam MS, Azmoon P, Gilder AS, Gonias SL (2016) LDL receptor-related protein-1 regulates NFkappaB and microRNA-155 in macrophages to control the inflammatory response. Proc Natl Acad Sci USA 113:1369–1374. https://doi.org/10.1073/pnas.1515480113

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Marcus J, Honigbaum S, Shroff S, Honke K, Rosenbluth J, Dupree JL (2006) Sulfatide is essential for the maintenance of CNS myelin and axon structure. Glia 53:372–381. https://doi.org/10.1002/glia.20292

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    May P, Rohlmann A, Bock HH, Zurhove K, Marth JD, Schomburg ED et al (2004) Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Mol Cell Biol 24:8872–8883

    CAS  Article  Google Scholar 

  50. 50.

    Na SY, Cao Y, Toben C, Nitschke L, Stadelmann C, Gold R et al (2008) Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system. Brain 131:2353–2365. https://doi.org/10.1093/brain/awn148

    Article  PubMed  Google Scholar 

  51. 51.

    Na SY, Eujen H, Gobel K, Meuth SG, Martens K, Wiendl H et al (2009) Antigen-specific blockade of lethal CD8 T-cell mediated autoimmunity in a mouse model of multiple sclerosis. J Immunol 182:6569–6575. https://doi.org/10.4049/jimmunol.0804200

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Raasch J, Zeller N, van Loo G, Merkler D, Mildner A, Erny D et al (2011) IkappaB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappaB in the central nervous system. Brain 134:1184–1198. https://doi.org/10.1093/brain/awq359

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15:1074–1077. https://doi.org/10.1038/nn.3168

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Sachs HH, Bercury KK, Popescu DC, Narayanan SP, Macklin WB (2014) A new model of cuprizone-mediated demyelination/remyelination. ASN Neuro. https://doi.org/10.1177/1759091414551955

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Seki SM, Stevenson M, Rosen AM, Arandjelovic S, Gemta L, Bullock TNJ et al (2017) Lineage-specific metabolic properties and vulnerabilities of T cells in the demyelinating central nervous system. J Immunol 198:4607–4617. https://doi.org/10.4049/jimmunol.1600825

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Skripuletz T, Gudi V, Hackstette D, Stangel M (2011) De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histol Histopathol 26:1585–1597

    CAS  PubMed  Google Scholar 

  58. 58.

    Song H, Li Y, Lee J, Schwartz AL, Bu G (2009) Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res 69:879–886. https://doi.org/10.1158/0008-5472.CAN-08-3379

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Subramanian M, Hayes CD, Thome JJ, Thorp E, Matsushima GK, Herz J et al (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J Clin Invest 124:1296–1308. https://doi.org/10.1172/JCI72051

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Yang L, Liu CC, Zheng H, Kanekiyo T, Atagi Y, Jia L et al (2016) LRP1 modulates the microglial immune response via regulation of JNK and NF-kappaB signaling pathways. J Neuroinflamm 13:304. https://doi.org/10.1186/s12974-016-0772-7

    CAS  Article  Google Scholar 

  61. 61.

    Zhang N, Bevan MJ (2011) CD8(+) T cells: foot soldiers of the immune system. Immunity 35:161–168. https://doi.org/10.1016/j.immuni.2011.07.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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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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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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Keywords

  • Demyelination
  • Multiple sclerosis
  • Oligodendrocyte progenitor cells
  • LRP1
  • Antigen cross-presentation
  • MHC1