Advertisement

The origin, fate, and contribution of macrophages to spinal cord injury pathology

  • Lindsay M. Milich
  • Christine B. Ryan
  • Jae K. LeeEmail author
Review

Abstract

Virtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in part by infiltrating monocyte-derived macrophages. It is now clear that these infiltrating macrophages have distinct functions from resident microglia and are capable of mediating both harmful and beneficial effects after injury. These divergent effects have been largely attributed to environmental cues, such as specific cytokines, that influence the macrophage polarization state. In this review, we also consider the possibility that different macrophage origins, including the spleen, bone marrow, and local self-renewal, may also affect macrophage fate, and ultimately their function that contribute to the complex pathobiology of spinal cord injury.

Keywords

Leukocytes Inflammation Myeloid cells Wound healing Glial and fibrotic scar Regeneration Peripheral Systemic 

Notes

Acknowledgements

This manuscript was supported by NINDS R01NS081040, the Buoniconti Fund, and The Miami Project to Cure Paralysis. CBR is supported by University of Miami Fellowship.

References

  1. 1.
    Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, Popovich PG (2006) Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma 23:635–659.  https://doi.org/10.1089/neu.2006.23.635 CrossRefPubMedGoogle Scholar
  2. 2.
    Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ (2010) Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 133:433–447.  https://doi.org/10.1093/brain/awp322 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Blomster LV, Brennan FH, Lao HW, Harle DW, Harvey AR, Ruitenberg MJ (2013) Mobilisation of the splenic monocyte reservoir and peripheral CX(3)CR1 deficiency adversely affects recovery from spinal cord injury. Exp Neurol 247:226–240.  https://doi.org/10.1016/j.expneurol.2013.05.002 CrossRefPubMedGoogle Scholar
  4. 4.
    Boato F, Rosenberger K, Nelissen S, Geboes L, Peters EM, Nitsch R et al (2013) Absence of IL-1beta positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury. J Neuroinflamm 10:6.  https://doi.org/10.1186/1742-2094-10-6 CrossRefGoogle Scholar
  5. 5.
    Bogie JF, Jorissen W, Mailleux J, Nijland PG, Zelcer N, Vanmierlo T et al (2013) Myelin alters the inflammatory phenotype of macrophages by activating PPARs. Acta Neuropathol Commun 1:43.  https://doi.org/10.1186/2051-5960-1-43 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bogie JF, Mailleux J, Wouters E, Jorissen W, Grajchen E, Vanmol J et al (2017) Scavenger receptor collectin placenta 1 is a novel receptor involved in the uptake of myelin by phagocytes. Sci Rep 7:44794.  https://doi.org/10.1038/srep44794 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Boven LA, Van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG (2006) Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 129:517–526.  https://doi.org/10.1093/brain/awh707 CrossRefPubMedGoogle Scholar
  8. 8.
    Braun DA, Fribourg M, Sealfon SC (2013) Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem 288:2986–2993.  https://doi.org/10.1074/jbc.M112.386573 CrossRefPubMedGoogle Scholar
  9. 9.
    Brown MS, Basu SK, Falck JR, Ho YK, Goldstein JL (1980) The scavenger cell pathway for lipoprotein degradation: specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages. J Supramol Struct 13:67–81.  https://doi.org/10.1002/jss.400130107 CrossRefPubMedGoogle Scholar
  10. 10.
    Brown MS, Goldstein JL (1979) Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci USA 76:3330–3337CrossRefPubMedGoogle Scholar
  11. 11.
    Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C et al (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA 109:2491–2496.  https://doi.org/10.1073/pnas.1113744109 CrossRefPubMedGoogle Scholar
  12. 12.
    Coste A, Dubourdeau M, Linas MD, Cassaing S, Lepert JC, Balard P et al (2003) PPAR gamma promotes mannose receptor gene expression in murine macrophages and contributes to the induction of this receptor by IL-13. Immunity 19:329–339.  https://doi.org/10.1016/S1074-7613(03)00229-2 CrossRefPubMedGoogle Scholar
  13. 13.
    da Costa CC, van der Laan LJ, Dijkstra CD, Bruck W (1997) The role of the mouse macrophage scavenger receptor in myelin phagocytosis. Eur J Neurosci 9:2650–2657CrossRefPubMedGoogle Scholar
  14. 14.
    Davies LC, Rosas M, Jenkins SJ, Liao CT, Scurr MJ, Brombacher F et al (2013) Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun 4:1886.  https://doi.org/10.1038/ncomms2877 CrossRefPubMedGoogle Scholar
  15. 15.
    Didangelos A, Iberl M, Vinsland E, Bartus K, Bradbury EJ (2014) Regulation of IL-10 by chondroitinase ABC promotes a distinct immune response following spinal cord injury. J Neurosci 34:16424–16432.  https://doi.org/10.1523/JNEUROSCI.2927-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Didangelos A, Puglia M, Iberl M, Sanchez-Bellot C, Roschitzki B, Bradbury EJ (2016) High-throughput proteomics reveal alarmins as amplifiers of tissue pathology and inflammation after spinal cord injury. Sci Rep 6:21607.  https://doi.org/10.1038/srep21607 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Donnelly DJ, Longbrake EE, Shawler TM, Kigerl KA, Lai W, Tovar CA et al (2011) Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS + macrophages. J Neurosci 31:9910–9922.  https://doi.org/10.1523/JNEUROSCI.2114-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Donnelly DJ, Popovich PG (2008) Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol 209:378–388.  https://doi.org/10.1016/j.expneurol.2007.06.009 CrossRefPubMedGoogle Scholar
  19. 19.
    Evans TA, Barkauskas DS, Myers JT, Hare EG, You JQ, Ransohoff RM et al (2014) High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp Neurol 254:109–120.  https://doi.org/10.1016/j.expneurol.2014.01.013 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fang P, Li X, Dai J, Cole L, Camacho JA, Zhang Y et al (2018) Immune cell subset differentiation and tissue inflammation. J Hematol Oncol 11:97.  https://doi.org/10.1186/s13045-018-0637-x CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fleming JC, Norenberg MD, Ramsay DA, Dekaban GA, Marcillo AE, Saenz AD et al (2006) The cellular inflammatory response in human spinal cords after injury. Brain 129:3249–3269.  https://doi.org/10.1093/brain/awl296 CrossRefPubMedGoogle Scholar
  22. 22.
    Francos-Quijorna I, Amo-Aparicio J, Martinez-Muriana A, Lopez-Vales R (2016) IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury. Glia 64:2079–2092.  https://doi.org/10.1002/glia.23041 CrossRefPubMedGoogle Scholar
  23. 23.
    Gaultier A, Wu XH, 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 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82CrossRefPubMedGoogle Scholar
  25. 25.
    Gensel JC, Nakamura S, Guan Z, van Rooijen N, Ankeny DP, Popovich PG (2009) Macrophages promote axon regeneration with concurrent neurotoxicity. J Neurosci 29:3956–3968.  https://doi.org/10.1523/JNEUROSCI.3992-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ginhoux F, Prinz M (2015) Origin of microglia: current concepts and past controversies. Cold Spring Harb Perspect Biol 7:a020537.  https://doi.org/10.1101/cshperspect.a020537 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Greenhalgh AD, Zarruk JG, Healy LM, Baskar Jesudasan SJ, Jhelum P, Salmon CK et al (2018) Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury. PLoS Biol 16:e2005264.  https://doi.org/10.1371/journal.pbio.2005264 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B et al (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:793–802CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gris D, Marsh DR, Oatway MA, Chen Y, Hamilton EF, Dekaban GA et al (2004) Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci 24:4043–4051.  https://doi.org/10.1523/JNEUROSCI.5343-03.2004 CrossRefPubMedGoogle Scholar
  30. 30.
    Guerrero AR, Uchida K, Nakajima H, Watanabe S, Nakamura M, Johnson WE et al (2012) Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. J Neuroinflamm 9:40.  https://doi.org/10.1186/1742-2094-9-40 CrossRefGoogle Scholar
  31. 31.
    Guo L, Rolfe AJ, Wang X, Tai W, Cheng Z, Cao K et al (2016) Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media. Mol Brain 9:48.  https://doi.org/10.1186/s13041-016-0233-3 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hawthorne AL, Popovich PG (2011) Emerging concepts in myeloid cell biology after spinal cord injury. Neurotherapeutics 8:252–261.  https://doi.org/10.1007/s13311-011-0032-6 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Healy LM, Perron G, Won SY, Michell-Robinson MA, Rezk A, Ludwin SK et al (2016) MerTK is a functional regulator of myelin phagocytosis by human myeloid cells. J Immunol 196:3375–3384.  https://doi.org/10.4049/jimmunol.1502562 CrossRefPubMedGoogle Scholar
  34. 34.
    Hervera A, De Virgiliis F, Palmisano I, Zhou L, Tantardini E, Kong G et al (2018) Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat Cell Biol 20:307–319.  https://doi.org/10.1038/s41556-018-0039-x CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hong LTA, Kim YM, Park HH, Hwang DH, Cui Y, Lee EM et al (2017) An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling. Nat Commun 8:533.  https://doi.org/10.1038/s41467-017-00583-8 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Iannotti CA, Clark M, Horn KP, van Rooijen N, Silver J, Steinmetz MP (2011) A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI. Exp Neurol 230:3–15.  https://doi.org/10.1016/j.expneurol.2010.03.010 CrossRefPubMedGoogle Scholar
  37. 37.
    Kezic J, McMenamin PG (2008) Differential turnover rates of monocyte-derived cells in varied ocular tissue microenvironments. J Leukoc Biol 84:721–729.  https://doi.org/10.1189/jlb.0308166 CrossRefPubMedGoogle Scholar
  38. 38.
    Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444.  https://doi.org/10.1523/JNEUROSCI.3257-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kigerl KA, McGaughy VM, Popovich PG (2006) Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J Comp Neurol 494:578–594.  https://doi.org/10.1002/cne.20827 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kopper TJ, Gensel JC (2018) Myelin as an inflammatory mediator: myelin interactions with complement, macrophages, and microglia in spinal cord injury. J Neurosci Res 96:969–977.  https://doi.org/10.1002/jnr.24114 CrossRefPubMedGoogle Scholar
  41. 41.
    Kostyk SK, Popovich PG, Stokes BT, Wei P, Jakeman LB (2008) Robust axonal growth and a blunted macrophage response are associated with impaired functional recovery after spinal cord injury in the MRL/MpJ mouse. Neuroscience 156:498–514.  https://doi.org/10.1016/j.neuroscience.2008.08.013 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kotter MR, Zhao C, van Rooijen N, Franklin RJ (2005) Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 18:166–175.  https://doi.org/10.1016/j.nbd.2004.09.019 CrossRefPubMedGoogle Scholar
  43. 43.
    Krzyszczyk P, Schloss R, Palmer A, Berthiaume F (2018) The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol 9:419.  https://doi.org/10.3389/fphys.2018.00419 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kwon MJ, Shin HY, Cui Y, Kim H, Thi AH, Choi JY et al (2015) CCL2 mediates neuron-macrophage interactions to drive proregenerative macrophage activation following preconditioning injury. J Neurosci 35:15934–15947.  https://doi.org/10.1523/JNEUROSCI.1924-15.2015 CrossRefPubMedGoogle Scholar
  45. 45.
    Landsman L, Bar-On L, Zernecke A, Kim KW, Krauthgamer R, Shagdarsuren E et al (2009) CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113:963–972.  https://doi.org/10.1182/blood-2008-07-170787 CrossRefPubMedGoogle Scholar
  46. 46.
    Lee SI, Jeong SR, Kan YM, Han DH, Jin BK, Namgung U et al (2010) Endogenous expression of interleukin-4 regulates macrophage activation and confines cavity formation after traumatic spinal cord injury. J Neurosci Res 88:2409–2419.  https://doi.org/10.1002/jnr.22411 CrossRefPubMedGoogle Scholar
  47. 47.
    Lee SM, Rosen S, Weinstein P, van Rooijen N, Noble-Haeusslein LJ (2011) Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma 28:1893–1907.  https://doi.org/10.1089/neu.2011.1860 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lee YS, Funk LH, Lee JK, Bunge MB (2018) Macrophage depletion and Schwann cell transplantation reduce cyst size after rat contusive spinal cord injury. Neural Regen Res 13:684–691.  https://doi.org/10.4103/1673-5374.230295 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ley K, Pramod AB, Croft M, Ravichandran KS, Ting JP (2016) How mouse macrophages sense what is going on. Front Immunol 7:204.  https://doi.org/10.3389/fimmu.2016.00204 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Li WW, Setzu A, Zhao C, Franklin RJ (2005) Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor cell responses and remyelination in a non-immune model of demyelination. J Neuroimmunol 158:58–66.  https://doi.org/10.1016/j.jneuroim.2004.08.011 CrossRefPubMedGoogle Scholar
  51. 51.
    Lindborg JA, Mack M, Zigmond RE (2017) Neutrophils are critical for myelin removal in a peripheral nerve injury model of wallerian degeneration. J Neurosci 37:10258–10277.  https://doi.org/10.1523/JNEUROSCI.2085-17.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Liu T, Zhang L, Joo D, Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther.  https://doi.org/10.1038/sigtrans.2017.23 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Lu X, Richardson PM (1993) Responses of macrophages in rat dorsal root ganglia following peripheral nerve injury. J Neurocytol 22:334–341CrossRefPubMedGoogle Scholar
  54. 54.
    Ma M, Wei P, Wei T, Ransohoff RM, Jakeman LB (2004) Enhanced axonal growth into a spinal cord contusion injury site in a strain of mouse (129X1/SvJ) with a diminished inflammatory response. J Comp Neurol 474:469–486.  https://doi.org/10.1002/cne.20149 CrossRefPubMedGoogle Scholar
  55. 55.
    Ma M, Wei T, Boring L, Charo IF, Ransohoff RM, Jakeman LB (2002) Monocyte recruitment and myelin removal are delayed following spinal cord injury in mice with CCR2 chemokine receptor deletion. J Neurosci Res 68:691–702.  https://doi.org/10.1002/jnr.10269 CrossRefPubMedGoogle Scholar
  56. 56.
    Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13.  https://doi.org/10.12703/p6-13 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Mawhinney LA, Thawer SG, Lu WY, Rooijen N, Weaver LC, Brown A et al (2012) Differential detection and distribution of microglial and hematogenous macrophage populations in the injured spinal cord of lys-EGFP-ki transgenic mice. J Neuropathol Exp Neurol 71:180–197.  https://doi.org/10.1097/NEN.0b013e3182479b41 CrossRefPubMedGoogle Scholar
  58. 58.
    Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173CrossRefPubMedGoogle Scholar
  59. 59.
    Mills CD, Shearer J, Evans R, Caldwell MD (1992) Macrophage arginine metabolism and the inhibition or stimulation of cancer. J Immunol 149:2709–2714PubMedGoogle Scholar
  60. 60.
    Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218.  https://doi.org/10.1038/nn.3469 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Mironets E, Osei-Owusu P, Bracchi-Ricard V, Fischer R, Owens EA, Ricard J et al (2018) Soluble TNFalpha signaling within the spinal cord contributes to the development of autonomic dysreflexia and ensuing vascular and immune dysfunction after spinal cord injury. J Neurosci 38:4146–4162.  https://doi.org/10.1523/JNEUROSCI.2376-17.2018 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Moore KJ, Sheedy FJ, Fisher EA (2013) Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13:709–721.  https://doi.org/10.1038/nri3520 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Mukhamedshina YO, Akhmetzyanova ER, Martynova EV, Khaiboullina SF, Galieva LR, Rizvanov AA (2017) Systemic and local cytokine profile following spinal cord injury in rats: a multiplex analysis. Front Neurol.  https://doi.org/10.3389/fneur.2017.00581 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Murray PJ (2006) Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 6:379–386.  https://doi.org/10.1016/j.coph.2006.01.010 CrossRefPubMedGoogle Scholar
  65. 65.
    Nguyen HX, O’Barr TJ, Anderson AJ (2007) Polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and TNF-alpha. J Neurochem 102:900–912.  https://doi.org/10.1111/j.1471-4159.2007.04643.x CrossRefPubMedGoogle Scholar
  66. 66.
    Niemi JP, DeFrancesco-Lisowitz A, Cregg JM, Howarth M, Zigmond RE (2016) Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism. Exp Neurol 275(Pt 1):25–37.  https://doi.org/10.1016/j.expneurol.2015.09.018 CrossRefPubMedGoogle Scholar
  67. 67.
    Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22:7526–7535CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Novrup HG, Bracchi-Ricard V, Ellman DG, Ricard J, Jain A, Runko E et al (2014) Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. J Neuroinflamm 11:159.  https://doi.org/10.1186/s12974-014-0159-6 CrossRefGoogle Scholar
  69. 69.
    Odegaard JI, Ricardo-Gonzalez RR, Eagle AR, Vats D, Morel CR, Goforth MH et al (2008) Alternative M2 activation of Kupffer cells by PPAR delta ameliorates obesity-induced insulin resistance. Cell Metab 7:496–507.  https://doi.org/10.1016/j.cmet.2008.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Papatheodorou A, Stein A, Bank M, Sison CP, Gibbs K, Davies P et al (2017) High-mobility group box 1 (HMGB1) is elevated systemically in persons with acute or chronic traumatic spinal cord injury. J Neurotrauma 34:746–754.  https://doi.org/10.1089/neu.2016.4596 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Perrin FE, Lacroix S, Aviles-Trigueros M, David S (2005) Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degeneration. Brain 128:854–866.  https://doi.org/10.1093/brain/awh407 CrossRefPubMedGoogle Scholar
  72. 72.
    Pineau I, Lacroix S (2007) Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. J Comp Neurol 500:267–285.  https://doi.org/10.1002/cne.21149 CrossRefPubMedGoogle Scholar
  73. 73.
    Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT (1999) Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 158:351–365.  https://doi.org/10.1006/exnr.1999.7118 CrossRefPubMedGoogle Scholar
  74. 74.
    Popovich PG, Hickey WF (2001) Bone marrow chimeric rats reveal the unique distribution of resident and recruited macrophages in the contused rat spinal cord. J Neuropathol Exp Neurol 60:676–685CrossRefPubMedGoogle Scholar
  75. 75.
    Porta C, Riboldi E, Ippolito A, Sica A (2015) Molecular and epigenetic basis of macrophage polarized activation. Semin Immunol 27:237–248.  https://doi.org/10.1016/j.smim.2015.10.003 CrossRefPubMedGoogle Scholar
  76. 76.
    PrabhuDas MR, Baldwin CL, Bollyky PL, Bowdish DME, Drickamer K, Febbraio M et al (2017) A consensus definitive classification of scavenger receptors and their roles in health and disease. J Immunol 198:3775–3789.  https://doi.org/10.4049/jimmunol.1700373 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M et al (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4:814–821CrossRefPubMedGoogle Scholar
  78. 78.
    Reichert F, Rotshenker S (2003) Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages. Neurobiol Dis 12:65–72CrossRefPubMedGoogle Scholar
  79. 79.
    Ren Y, Stuart L, Lindberg FP, Rosenkranz AR, Chen Y, Mayadas TN et al (2001) Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of beta 2 integrins. J Immunol 166:4743–4750CrossRefPubMedGoogle Scholar
  80. 80.
    Richardson PM, Issa VM (1984) Peripheral injury enhances central regeneration of primary sensory neurones. Nature 309:791–793CrossRefPubMedGoogle Scholar
  81. 81.
    Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL et al (2013) Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 19:1166–1172.  https://doi.org/10.1038/nm.3258 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Rolls A, Shechter R, London A, Segev Y, Jacob-Hirsch J, Amariglio N et al (2008) Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med 5:e171.  https://doi.org/10.1371/journal.pmed.0050171 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Rotshenker S (2003) Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease. J Mol Neurosci 21:65–72.  https://doi.org/10.1385/JMN:21:1:65 CrossRefPubMedGoogle Scholar
  84. 84.
    Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL et al (2010) Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5:e13693.  https://doi.org/10.1371/journal.pone.0013693 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Sanz E, Yang L, Su T, Morris DR, McKnight GS, Amieux PS (2009) Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc Natl Acad Sci USA 106:13939–13944.  https://doi.org/10.1073/pnas.0907143106 CrossRefPubMedGoogle Scholar
  86. 86.
    Savill J, Hogg N, Ren Y, Haslett C (1992) Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Investig 90:1513–1522.  https://doi.org/10.1172/JCI116019 CrossRefPubMedGoogle Scholar
  87. 87.
    Schwartz M (2003) Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab 23:385–394.  https://doi.org/10.1097/01.WCB.0000061881.75234.5E CrossRefPubMedGoogle Scholar
  88. 88.
    Schwartz M, Raposo C (2014) Protective autoimmunity: a unifying model for the immune network involved in CNS repair. Neuroscientist 20:343–358.  https://doi.org/10.1177/1073858413516799 CrossRefPubMedGoogle Scholar
  89. 89.
    Schwartz M, Yoles E (2005) Macrophages and dendritic cells treatment of spinal cord injury: from the bench to the clinic. Acta Neurochir Suppl 93:147–150CrossRefPubMedGoogle Scholar
  90. 90.
    Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G et al (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6:e1000113.  https://doi.org/10.1371/journal.pmed.1000113 CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J et al (2013) Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38:555–569.  https://doi.org/10.1016/j.immuni.2013.02.012 CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A et al (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155–161.  https://doi.org/10.1038/ni.1836 CrossRefPubMedGoogle Scholar
  93. 93.
    Sun X, Wang X, Chen T, Li T, Cao K, Lu A et al (2010) Myelin activates FAK/Akt/NF-kappaB pathways and provokes CR3-dependent inflammatory response in murine system. PLoS One 5:e9380.  https://doi.org/10.1371/journal.pone.0009380 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P et al (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325:612–616.  https://doi.org/10.1126/science.1175202 CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Torres-Espin A, Forero J, Fenrich KK, Lucas-Osma AM, Krajacic A, Schmidt E et al (2018) Eliciting inflammation enables successful rehabilitative training in chronic spinal cord injury. Brain 141:1946–1962.  https://doi.org/10.1093/brain/awy128 CrossRefPubMedGoogle Scholar
  96. 96.
    Tymoszuk P, Evens H, Marzola V, Wachowicz K, Wasmer MH, Datta S et al (2014) In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors. Eur J Immunol 44:2247–2262.  https://doi.org/10.1002/eji.201344304 CrossRefPubMedGoogle Scholar
  97. 97.
    Wang C, Yu X, Cao Q, Wang Y, Zheng G, Tan TK et al (2013) Characterization of murine macrophages from bone marrow, spleen and peritoneum. BMC Immunol 14:6.  https://doi.org/10.1186/1471-2172-14-6 CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Wang N, Liang H, Zen K (2014) Molecular mechanisms that influence the macrophage m1–m2 polarization balance. Front Immunol 5:614.  https://doi.org/10.3389/fimmu.2014.00614 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Wang X, Cao K, Sun X, Chen Y, Duan Z, Sun L et al (2015) Macrophages in spinal cord injury: phenotypic and functional change from exposure to myelin debris. Glia 63:635–651.  https://doi.org/10.1002/glia.22774 CrossRefPubMedGoogle Scholar
  100. 100.
    Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F et al (2010) Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116:4815–4828.  https://doi.org/10.1182/blood-2009-11-253534 CrossRefPubMedGoogle Scholar
  101. 101.
    Yan P, Liu N, Kim GM, Xu J, Xu J, Li Q et al (2003) Expression of the type 1 and type 2 receptors for tumor necrosis factor after traumatic spinal cord injury in adult rats. Exp Neurol 183:286–297CrossRefPubMedGoogle Scholar
  102. 102.
    Yang J, Zhang L, Yu C, Yang XF, Wang H (2014) Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2:1.  https://doi.org/10.1186/2050-7771-2-1 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D et al (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4:551–556.  https://doi.org/10.1038/ni938 CrossRefPubMedGoogle Scholar
  104. 104.
    Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A et al (2001) Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 21:3740–3748CrossRefPubMedGoogle Scholar
  105. 105.
    Zhou Q, Xiang H, Li A, Lin W, Huang Z, Guo J et al (2018) Activating adiponectin signaling with exogenous AdipoRon reduces myelin lipid accumulation and suppresses macrophage recruitment after spinal cord injury. J Neurotrauma.  https://doi.org/10.1089/neu.2018.5783 CrossRefPubMedGoogle Scholar
  106. 106.
    Zhu Y, Lyapichev K, Lee DH, Motti D, Ferraro NM, Zhang Y et al (2017) Macrophage transcriptional profile identifies lipid catabolic pathways that can be therapeutically targeted after spinal cord injury. J Neurosci 37:2362–2376.  https://doi.org/10.1523/JNEUROSCI.2751-16.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Zhu Y, Soderblom C, Krishnan V, Ashbaugh J, Bethea JR, Lee JK (2015) Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis 74:114–125.  https://doi.org/10.1016/j.nbd.2014.10.024 CrossRefPubMedGoogle Scholar
  108. 108.
    Zigmond RE, Echevarria FD (2019) Macrophage biology in the peripheral nervous system after injury. Prog Neurobiol 173:102–121.  https://doi.org/10.1016/j.pneurobio.2018.12.001 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Miami Project to Cure Paralysis, Department of Neurological SurgeryUniversity of Miami School of MedicineMiamiUSA

Personalised recommendations