, Volume 15, Issue 3, pp 541–553 | Cite as

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

  • Michael B. Orr
  • John C. Gensel


Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes.

Key Words

Macrophage human chondroitinase ABC (chABC) azithromycin glial limitans traumatic brain injury. 



This work is supported by NIH R01 NS091582. Stipend support for MO from the Kentucky Spinal Cord and Head Injury Research Trust and the University of Kentucky College of Medicine Fellowship for Excellence in Graduate Research. The authors would like to thank Phillip Popovich and the editors, Mar Cortes, Keith Tansey, and Guillermo Garcia-Alias, for their endorsements.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2018_631_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1225 kb)


  1. 1.
    Bell RD, Winkler EA, Sagare AP, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 68(3), 409–427 (2010).PubMedPubMedCentralGoogle Scholar
  2. 2.
    Göritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisén J. A pericyte origin of spinal cord scar tissue. Science. 333(6039), 238–242 (2011).PubMedGoogle Scholar
  3. 3.
    Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. 443(7112), 700–704 (2006).PubMedPubMedCentralGoogle Scholar
  4. 4.
    Oyinbo CA. Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol Exp (Wars). 71(2), 281–299 (2011).PubMedGoogle Scholar
  5. 5.
    Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ. Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain. 133(Pt 2), 433–447 (2010).PubMedPubMedCentralGoogle Scholar
  6. 6.
    Fleming JC, Norenberg MD, Ramsay DA, et al. The cellular inflammatory response in human spinal cords after injury. Brain. 129(Pt 12), 3249–3269 (2006).PubMedGoogle Scholar
  7. 7.
    Sroga JM, Jones TB, Kigerl KA, McGaughy VM, Popovich PG. Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J Comp Neurol. 462(2), 223–240 (2003).PubMedGoogle Scholar
  8. 8.
    Soderblom C, Luo X, Blumenthal E, et al. Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. Journal of Neuroscience. 33(34), 13882–13887 (2013).PubMedGoogle Scholar
  9. 9.
    Bruce JH, Norenberg MD, Kraydieh S, Puckett W, Marcillo A, Dietrich D. Schwannosis: role of gliosis and proteoglycan in human spinal cord injury. J Neurotrauma. 17(9), 781–788 (2000).PubMedGoogle Scholar
  10. 10.
    Buss A, Pech K, Kakulas BA, et al. Growth-modulating molecules are associated with invading Schwann cells and not astrocytes in human traumatic spinal cord injury. Brain. 130(Pt 4), 940–953 (2007).PubMedGoogle Scholar
  11. 11.
    Zhang S-X, Huang F, Gates M, Holmberg EG. Role of endogenous Schwann cells in tissue repair after spinal cord injury. Neural Regen Res. 8(2), 177–185 (2013).PubMedPubMedCentralGoogle Scholar
  12. 12.
    Beattie MS, Bresnahan JC, Komon J, et al. Endogenous repair after spinal cord contusion injuries in the rat. Exp Neurol. 148(2), 453–463 (1997).PubMedGoogle Scholar
  13. 13.
    Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 532(7598), 195–200 (2016).PubMedPubMedCentralGoogle Scholar
  14. 14.
    Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 81(2), 229–248 (2014).PubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhu Y, Soderblom C, Krishnan V, Ashbaugh J, Bethea JR, Lee JK. Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis. 74C, 114–125 (2014).Google Scholar
  16. 16.
    Zamanian JL, Xu L, Foo LC, et al. Genomic analysis of reactive astrogliosis. Journal of Neuroscience. 32(18), 6391–6410 (2012).PubMedGoogle Scholar
  17. 17.
    David S, Aguayo AJ. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science. 214(4523), 931–933 (1981).PubMedGoogle Scholar
  18. 18.
    Abnet K, Fawcett JW, Dunnett SB. Interactions between meningeal cells and astrocytes in vivo and in vitro. Brain Res. Dev. Brain Res. 59(2), 187–196 (1991).PubMedGoogle Scholar
  19. 19.
    Bundesen LQ, Scheel TA, Bregman BS, Kromer LF. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. Journal of Neuroscience. 23(21), 7789–7800 (2003).PubMedGoogle Scholar
  20. 20.
    Shearer MC, Fawcett JW. The astrocyte/meningeal cell interface—a barrier to successful nerve regeneration? Cell Tissue Res. 305(2), 267–273 (2001).PubMedGoogle Scholar
  21. 21.
    Kimura-Kuroda J, Teng X, Komuta Y, et al. An in vitro model of the inhibition of axon growth in the lesion scar formed after central nervous system injury. Mol. Cell. Neurosci. 43(2), 177–187 (2010).PubMedGoogle Scholar
  22. 22.
    Kawano H, Kimura-Kuroda J, Komuta Y, et al. Role of the lesion scar in the response to damage and repair of the central nervous system. Cell Tissue Res. 349(1), 169–180 (2012).PubMedPubMedCentralGoogle Scholar
  23. 23.
    Bradbury EJ, Moon LDF, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 416(6881), 636–640 (2002).PubMedGoogle Scholar
  24. 24.
    Tang X, Davies JE, Davies SJA. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue. J Neurosci Res. 71(3), 427–444 (2003).PubMedGoogle Scholar
  25. 25.
    McKeon RJ, Jurynec MJ, Buck CR. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. Journal of Neuroscience. 19(24), 10778–10788 (1999).PubMedGoogle Scholar
  26. 26.
    Zhu Y, Soderblom C, Trojanowsky M, Lee D-H, Lee JK. Fibronectin matrix assembly after spinal cord injury. J Neurotrauma. 32(15), 1158–1167 (2015).PubMedPubMedCentralGoogle Scholar
  27. 27.
    Schreiber J, Schachner M, Schumacher U, Lorke DE. Extracellular matrix alterations, accelerated leukocyte infiltration and enhanced axonal sprouting after spinal cord hemisection in tenascin-C-deficient mice. Acta Histochem. 115(8), 865–878 (2013).PubMedGoogle Scholar
  28. 28.
    Weidner N, Grill RJ, Tuszynski MH. Elimination of basal lamina and the collagen “scar” after spinal cord injury fails to augment corticospinal tract regeneration. Exp Neurol. 160(1), 40–50 (1999).PubMedGoogle Scholar
  29. 29.
    Klapka N, Hermanns S, Straten G, et al. Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery. Eur J Neurosci. 22(12), 3047–3058 (2005).PubMedGoogle Scholar
  30. 30.
    Loy DN, Crawford CH, Darnall JB, Burke DA, Onifer SM, Whittemore SR. Temporal progression of angiogenesis and basal lamina deposition after contusive spinal cord injury in the adult rat. J Comp Neurol. 445(4), 308–324 (2002).PubMedGoogle Scholar
  31. 31.
    Klapka N, Müller HW. Collagen matrix in spinal cord injury. J Neurotrauma. 23(3–4), 422–435 (2006).PubMedGoogle Scholar
  32. 32.
    Ruschel J, Hellal F, Flynn KC, et al. Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science. 348(6232), 347–352 (2015).PubMedPubMedCentralGoogle Scholar
  33. 33.
    McKeon RJ, Schreiber RC, Rudge JS, Silver J. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci. 11(11), 3398–3411 (1991).PubMedGoogle Scholar
  34. 34.
    Stichel CC, Niermann H, D'Urso D, Lausberg F, Hermanns S, Müller HW. Basal membrane-depleted scar in lesioned CNS: characteristics and relationships with regenerating axons. Neuroscience. 93(1), 321–333 (1999).PubMedGoogle Scholar
  35. 35.
    Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 209(2), 378–388 (2008).PubMedGoogle Scholar
  36. 36.
    Mawhinney LA, Thawer SG, Lu W-Y, et al. 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(3), 180–197 (2012).PubMedGoogle Scholar
  37. 37.
    Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. Journal of Neuroscience. 29(43), 13435–13444 (2009).PubMedGoogle Scholar
  38. 38.
    Carlson SL, Parrish ME, Springer JE, Doty K, Dossett L. Acute inflammatory response in spinal cord following impact injury. Exp Neurol. 151(1), 77–88 (1998).PubMedGoogle Scholar
  39. 39.
    Taoka Y, Okajima K, Uchiba M, et al. Role of neutrophils in spinal cord injury in the rat. Neuroscience. 79(4), 1177–1182 (1997).PubMedGoogle Scholar
  40. 40.
    Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol. 158(2), 351–365 (1999).PubMedGoogle Scholar
  41. 41.
    Wang G, Zhang J, Hu X, et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab. 33(12), 1864–1874 (2013).PubMedPubMedCentralGoogle Scholar
  42. 42.
    Fitch MT, Doller C, Combs CK, Landreth GE, Silver J. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci. 19(19), 8182–8198 (1999).PubMedGoogle Scholar
  43. 43.
    Soderblom C, Lee D-H, Dawood A, et al. 3D imaging of axons in transparent spinal cords from rodents and nonhuman primates. eNeuro. 2(2) (2015).Google Scholar
  44. 44.
    Decimo I, Bifari F, Rodriguez FJ, et al. Nestin- and doublecortin-positive cells reside in adult spinal cord meninges and participate in injury-induced parenchymal reaction. STEM CELLS. 29(12), 2062–2076 (2011).PubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhang B, Bailey WM, Kopper TJ, Orr MB, Feola DJ, Gensel JC. Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury. J Neuroinflammation. 12, 218 (2015).PubMedPubMedCentralGoogle Scholar
  46. 46.
    Bloom O. Non-mammalian model systems for studying neuro-immune interactions after spinal cord injury. Exp Neurol. 258, 130–140 (2014).PubMedGoogle Scholar
  47. 47.
    Goldshmit Y, Sztal TE, Jusuf PR, Hall TE, Nguyen-Chi M, Currie PD. Fgf-dependent glial cell bridges facilitate spinal cord regeneration in zebrafish. Journal of Neuroscience. 32(22), 7477–7492 (2012).PubMedGoogle Scholar
  48. 48.
    Zukor KA, Kent DT, Odelberg SJ. Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts. Neural Dev. 6, 1 (2011).PubMedPubMedCentralGoogle Scholar
  49. 49.
    Logan A, Berry M, Gonzalez AM, Frautschy SA, Sporn MB, Baird A. Effects of transforming growth factor beta 1 on scar production in the injured central nervous system of the rat. Eur J Neurosci. 6(3), 355–363 (1994).PubMedGoogle Scholar
  50. 50.
    East E, Golding JP, Phillips JB. A versatile 3D culture model facilitates monitoring of astrocytes undergoing reactive gliosis. J Tissue Eng Regen Med. 3(8), 634–646 (2009).PubMedPubMedCentralGoogle Scholar
  51. 51.
    Renault-Mihara F, Mukaino M, Shinozaki M, et al. Regulation of RhoA by STAT3 coordinates glial scar formation. J Cell Biol. 216(8), 2533–2550 (2017).PubMedPubMedCentralGoogle Scholar
  52. 52.
    Wanner IB, Anderson MA, Song B, et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. Journal of Neuroscience. 33(31), 12870–12886 (2013).PubMedGoogle Scholar
  53. 53.
    Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 24(9), 2143–2155 (2004).PubMedGoogle Scholar
  54. 54.
    Bott K, Upton Z, Schrobback K, et al. The effect of matrix characteristics on fibroblast proliferation in 3D gels. Biomaterials. 31(32), 8454–8464 (2010).PubMedGoogle Scholar
  55. 55.
    Harris GM, Madigan NN, Lancaster KZ, et al. Nerve guidance by a decellularized fibroblast extracellular matrix. Matrix Biol. 60-61, 176–189 (2017).PubMedGoogle Scholar
  56. 56.
    Franze K, Janmey PA, Guck J. Mechanics in neuronal development and repair. Annu Rev Biomed Eng. 15, 227–251 (2013).PubMedGoogle Scholar
  57. 57.
    Tremble P, Chiquet-Ehrismann R, Werb Z. The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts. Mol. Biol. Cell. 5(4), 439–453 (1994).PubMedPubMedCentralGoogle Scholar
  58. 58.
    Trebaul A, Chan EK, Midwood KS. Regulation of fibroblast migration by tenascin-C. Biochem. Soc. Trans. 35(Pt 4), 695–697 (2007).PubMedGoogle Scholar
  59. 59.
    Kalembeyi I, Inada H, Nishiura R, Imanaka-Yoshida K, Sakakura T, Yoshida T. Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1. Int. J. Cancer. 105(1), 53–60 (2003).PubMedGoogle Scholar
  60. 60.
    Ogier C, Bernard A, Chollet A-M, et al. Matrix metalloproteinase-2 (MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins. Glia. 54(4), 272–284 (2006).PubMedGoogle Scholar
  61. 61.
    Goussev S, Hsu J-YC, Lin Y, et al. Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J. Neurosurg. 99(2 Suppl), 188–197 (2003).PubMedPubMedCentralGoogle Scholar
  62. 62.
    Tezel G, Hernandez MR, Wax MB. In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head. Glia. 34(3), 178–189 (2001).PubMedGoogle Scholar
  63. 63.
    Takenaga K, Kozlova EN. Role of intracellular S100A4 for migration of rat astrocytes. Glia. 53(3), 313–321 (2006).PubMedGoogle Scholar
  64. 64.
    Yu F, Kamada H, Niizuma K, Endo H, Chan PH. Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma. 25(3), 184–195 (2008).PubMedPubMedCentralGoogle Scholar
  65. 65.
    Hsu J-YC, McKeon R, Goussev S, et al. Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. Journal of Neuroscience. 26(39), 9841–9850 (2006).PubMedGoogle Scholar
  66. 66.
    Zhang H, Trivedi A, Lee J-U, et al. Matrix metalloproteinase-9 and stromal cell-derived factor-1 act synergistically to support migration of blood-borne monocytes into the injured spinal cord. Journal of Neuroscience. 31(44), 15894–15903 (2011).PubMedGoogle Scholar
  67. 67.
    Shechter R, Raposo C, London A, Sagi I, Schwartz M. The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair. PLoS ONE. 6(12), e27969 (2011).PubMedPubMedCentralGoogle Scholar
  68. 68.
    Rolls A, Shechter R, London A, et al. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 5(8), e171 (2008).PubMedPubMedCentralGoogle Scholar
  69. 69.
    Tasdemir-Yilmaz OE, Freeman MR. Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev. 28(1), 20–33 (2014).PubMedPubMedCentralGoogle Scholar
  70. 70.
    Clark P, Britland S, Connolly P. Growth cone guidance and neuron morphology on micropatterned laminin surfaces. Journal of Cell Science. 105 ( Pt 1), 203–212 (1993).PubMedGoogle Scholar
  71. 71.
    Chung W-S, Clarke LE, Wang GX, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 504(7480), 394–400 (2013).PubMedPubMedCentralGoogle Scholar
  72. 72.
    Bush TG, Puvanachandra N, Horner CH, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron. 23(2), 297–308 (1999).PubMedGoogle Scholar
  73. 73.
    Alilain WJ, Horn KP, Hu H, Dick TE, Silver J. Functional regeneration of respiratory pathways after spinal cord injury. Nature. 475(7355), 196–200 (2011).PubMedPubMedCentralGoogle Scholar
  74. 74.
    Manwaring ME, Walsh JF, Tresco PA. Contact guidance induced organization of extracellular matrix. Biomaterials. 25(17), 3631–3638 (2004).PubMedGoogle Scholar
  75. 75.
    Gonzalez-Perez F, Udina E, Navarro X. Extracellular matrix components in peripheral nerve regeneration. Int. Rev. Neurobiol. 108, 257–275 (2013).PubMedGoogle Scholar
  76. 76.
    Shen D, Wang X, Gu X. Scar-modulating treatments for central nervous system injury. Neurosci Bull. 30(6), 967–984 (2014).PubMedPubMedCentralGoogle Scholar
  77. 77.
    O’Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J Clin Invest. 127(9), 3259–3270 (2017).PubMedGoogle Scholar
  78. 78.
    Buss A, Brook GA, Kakulas B, et al. Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain. 127(Pt 1), 34–44 (2004).PubMedGoogle Scholar
  79. 79.
    Buss A, Pech K, Kakulas BA, et al. NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury. BMC Neurol. 9, 32 (2009).PubMedPubMedCentralGoogle Scholar
  80. 80.
    Norenberg MD, Smith J, Marcillo A. The pathology of human spinal cord injury: defining the problems. J Neurotrauma. 21(4), 429–440 (2004).PubMedGoogle Scholar
  81. 81.
    Guest JD, Hiester ED, Bunge RP. Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp Neurol. 192(2), 384–393 (2005).PubMedGoogle Scholar
  82. 82.
    Jones LL, Margolis RU, Tuszynski MH. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol. 182(2), 399–411 (2003).PubMedGoogle Scholar
  83. 83.
    Shen Y, Tenney AP, Busch SA, et al. PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science. 326(5952), 592–596 (2009).PubMedPubMedCentralGoogle Scholar
  84. 84.
    McKillop WM, Dragan M, Schedl A, Brown A. Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury. Glia. 61(2), 164–177 (2013).PubMedGoogle Scholar
  85. 85.
    Takeuchi K, Yoshioka N, Higa Onaga S, et al. Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury. Nat Commun. 4, 2740 (2013).PubMedPubMedCentralGoogle Scholar
  86. 86.
    Oudega M, Chao OY, Avison DL, et al. Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury. Exp Neurol. 237(1), 170–179 (2012).PubMedGoogle Scholar
  87. 87.
    Grimpe B, Silver J. A novel DNA enzyme reduces glycosaminoglycan chains in the glial scar and allows microtransplanted dorsal root ganglia axons to regenerate beyond lesions in the spinal cord. Journal of Neuroscience. 24(6), 1393–1397 (2004).PubMedGoogle Scholar
  88. 88.
    Bradbury EJ, Carter LM. Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res. Bull. 84(4–5), 306–316 (2011).PubMedGoogle Scholar
  89. 89.
    Carter LM, Starkey ML, Akrimi SF, Davies M, Mcmahon SB, Bradbury EJ. The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. Journal of Neuroscience. 28(52), 14107–14120 (2008).PubMedGoogle Scholar
  90. 90.
    Bartus K, James ND, Didangelos A, et al. Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology and modulates macrophage phenotype following spinal cord contusion injury. Journal of Neuroscience. 34(14), 4822–4836 (2014).PubMedGoogle Scholar
  91. 91.
    Xu X, Bass B, McKillop WM, et al. Sox9 knockout mice have improved recovery following stroke. Exp Neurol. 303, 59–71 (2018).PubMedGoogle Scholar
  92. 92.
    Didangelos A, Iberl M, Vinsland E, Bartus K, Bradbury EJ. Regulation of IL-10 by chondroitinase ABC promotes a distinct Immune response following spinal cord injury. Journal of Neuroscience. 34(49), 16424–16432 (2014).PubMedGoogle Scholar
  93. 93.
    Shechter R, London A, Varol C, et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6(7), e1000113 (2009).PubMedPubMedCentralGoogle Scholar
  94. 94.
    Gensel JC, Kigerl KA, Mandrekar-Colucci SS, Gaudet AD, Popovich PG. Achieving CNS axon regeneration by manipulating convergent neuro-immune signaling. Cell Tissue Res. 349(1), 201–213 (2012).PubMedGoogle Scholar
  95. 95.
    Gensel JC, Donnelly DJ, Popovich PG. Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages. Expert Opin. Ther. Targets. 15(4), 505–518 (2011).PubMedGoogle Scholar
  96. 96.
    Hesp ZC, Yoseph RY, Suzuki R, Wilson C, Nishiyama A, McTigue DM. Proliferating NG2 cell-dependent angiogenesis and scar formation alter axon growth and functional recovery after spinal cord injury in mice. Journal of Neuroscience. (2017).Google Scholar
  97. 97.
    Zhao W, Chai Y, Hou Y, et al. Mechanisms responsible for the inhibitory effects of epothilone B on scar formation after spinal cord injury. Neural Regen Res. 12(3), 478–485 (2017).PubMedPubMedCentralGoogle Scholar
  98. 98.
    Ruschel J, Bradke F. Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury. Exp Neurol. (2017).Google Scholar
  99. 99.
    Sandner B, Puttagunta R, Motsch M, et al. Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats. Exp Neurol. (2018).Google Scholar
  100. 100.
    Hao J, Li B, Duan H-Q, et al. Mechanisms underlying the promotion of functional recovery by deferoxamine after spinal cord injury in rats. Neural Regen Res. 12(6), 959–968 (2017).PubMedPubMedCentralGoogle Scholar
  101. 101.
    Falnikar A, Li K, Lepore AC. Therapeutically targeting astrocytes with stem and progenitor cell transplantation following traumatic spinal cord injury. Brain Res. 1619, 91–103 (2015).PubMedGoogle Scholar
  102. 102.
    Hill CE, Proschel C, Noble M, et al. Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol. 190(2), 289–310 (2004).PubMedGoogle Scholar
  103. 103.
    Xiao Z, Tang F, Tang J, et al. One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Sci China Life Sci. 59(7), 647–655 (2016).PubMedGoogle Scholar
  104. 104.
    Zhao Y, Tang F, Xiao Z, et al. Clinical study of NeuroRegen scaffold combined with human mesenchymal stem cells for the repair of chronic complete spinal cord injury. Cell Transplant. 26(5), 891–900 (2017).PubMedPubMedCentralGoogle Scholar
  105. 105.
    Haggerty AE, Marlow MM, Oudega M. Extracellular matrix components as therapeutics for spinal cord injury. Neurosci Lett. 652, 50–55 (2017).PubMedGoogle Scholar
  106. 106.
    Kigerl KA, Popovich PG. Toll-like receptors in spinal cord injury. Curr. Top. Microbiol. Immunol. 336, 121–136 (2009).PubMedGoogle Scholar
  107. 107.
    Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW. Pattern recognition receptors and central nervous system repair. Exp Neurol. 258, 5–16 (2014).PubMedPubMedCentralGoogle Scholar
  108. 108.
    Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32(12), 638–647 (2009).PubMedPubMedCentralGoogle Scholar
  109. 109.
    David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 12(7), 388–399 (2011).PubMedGoogle Scholar
  110. 110.
    Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 1619, 1–11 (2015).PubMedGoogle Scholar
  111. 111.
    Mabon PJ, Weaver LC, Dekaban GA. Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin alphaD: a potential new anti-inflammatory treatment. Exp Neurol. 166(1), 52–64 (2000).PubMedGoogle Scholar
  112. 112.
    Yang L, Blumbergs PC, Jones NR, Manavis J, Sarvestani GT, Ghabriel MN. Early expression and cellular localization of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in human traumatic spinal cord injury. Spine. 29(9), 966–971 (2004).PubMedGoogle Scholar
  113. 113.
    Kigerl KA, McGaughy VM, Popovich PG. Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J Comp Neurol. 494(4), 578–594 (2006).PubMedPubMedCentralGoogle Scholar
  114. 114.
    Gensel JC, Popovich PG. Controversies on the role of inflammation in the injured spinal cord. In: Traumatic brain and spinal cord injury: challenges and developments in research. Morganti-Kossmann MC, Maas AI, Raghupathi R (Eds.). Cambrige Press, New York, 272–279.Google Scholar
  115. 115.
    de Castro R, Hughes MG, Xu GY, et al. Evidence that infiltrating neutrophils do not release reactive oxygen species in the site of spinal cord injury. Exp Neurol. 190(2), 414–424 (2004).PubMedGoogle Scholar
  116. 116.
    Kubota K, Saiwai H, Kumamaru H, et al. Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury. Spine. 37(16), 1363–1369 (2012).PubMedGoogle Scholar
  117. 117.
    Prüss H, Kopp MA, Brommer B, et al. Non-resolving aspects of acute inflammation after spinal cord injury (SCI): indices and resolution plateau. Brain Pathology (Zurich, Switzerland). 21(6), 652–660 (2011).Google Scholar
  118. 118.
    Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).PubMedGoogle Scholar
  119. 119.
    Gensel JC, Nakamura S, Guan Z, Van Rooijen N, Ankeny DP, Popovich PG. Macrophages promote axon regeneration with concurrent neurotoxicity. Journal of Neuroscience. 29(12), 3956–3968 (2009).PubMedGoogle Scholar
  120. 120.
    Greenhalgh AD, Passos Dos Santos R, Zarruk JG, Salmon CK, Kroner A, David S. Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease. Brain Behav Immun. (2016).Google Scholar
  121. 121.
    Ren Y, Young W. Managing inflammation after spinal cord injury through manipulation of macrophage function. Neural Plasticity. 2013, 945034 (2013).PubMedPubMedCentralGoogle Scholar
  122. 122.
    Benowitz LI, Popovich PG. Inflammation and axon regeneration. Curr. Opin. Neurol. 24(6), 577–583 (2011).PubMedGoogle Scholar
  123. 123.
    Huang W, Vodovotz Y, Kusturiss MB, et al. Identification of distinct monocyte phenotypes and correlation with circulating cytokine profiles in acute response to spinal cord injury: a pilot study. PM&R. 6(4), 332–341 (2014).Google Scholar
  124. 124.
    Kigerl K, Popovich P. Drug evaluation: ProCord—a potential cell-based therapy for spinal cord injury. IDrugs. 9(5), 354–360 (2006).PubMedGoogle Scholar
  125. 125.
    Rapalino O, Lazarov-Spiegler O, Agranov E, et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 4(7), 814–821 (1998).PubMedGoogle Scholar
  126. 126.
    Rabchevsky AG, Streit WJ. Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res. 47(1), 34–48 (1997).PubMedGoogle Scholar
  127. 127.
    Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N. Engl. J. Med. 322(20), 1405–1411 (1990).PubMedGoogle Scholar
  128. 128.
    Bowers CA, Kundu B, Hawryluk GWJ. Methylprednisolone for acute spinal cord injury: an increasingly philosophical debate. Neural Regen Res. 11(6), 882–885 (2016).PubMedPubMedCentralGoogle Scholar
  129. 129.
    Geremia NM, Bao F, Rosenzweig TE, et al. CD11d antibody treatment improves recovery in spinal cord-injured mice. J Neurotrauma. 29(3), 539–550 (2012).PubMedGoogle Scholar
  130. 130.
    Bao F, Brown A, Dekaban GA, Omana V, Weaver LC. CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury. Exp Neurol. 231(2), 272–283 (2011).PubMedPubMedCentralGoogle Scholar
  131. 131.
    Shultz SR, Bao F, Weaver LC, Cain DP, Brown A. Treatment with an anti-CD11d integrin antibody reduces neuroinflammation and improves outcome in a rat model of repeated concussion. J Neuroinflammation. 10, 26 (2013).PubMedPubMedCentralGoogle Scholar
  132. 132.
    Bao F, Shultz SR, Hepburn JD, et al. A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats. J Neurotrauma. 29(14), 2375–2392 (2012).PubMedPubMedCentralGoogle Scholar
  133. 133.
    Saville LR, Pospisil CH, Mawhinney LA, et al. A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment. J Neuroimmunol. 156(1–2), 42–57 (2004).PubMedGoogle Scholar
  134. 134.
    Bao F, Dekaban GA, Weaver LC. Anti-CD11d antibody treatment reduces free radical formation and cell death in the injured spinal cord of rats. J Neurochem. 94(5), 1361–1373 (2005).PubMedGoogle Scholar
  135. 135.
    Oatway MA, Chen Y, Bruce JC, Dekaban GA, Weaver LC. Anti-CD11d integrin antibody treatment restores normal serotonergic projections to the dorsal, intermediate, and ventral horns of the injured spinal cord. Journal of Neuroscience. 25(3), 637–647 (2005).PubMedGoogle Scholar
  136. 136.
    Gris D, Marsh DR, Oatway MA, et al. Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci. 24(16), 4043–4051 (2004).PubMedGoogle Scholar
  137. 137.
    Ditor DS, Bao F, Chen Y, Dekaban GA, Weaver LC. A therapeutic time window for anti-CD 11d monoclonal antibody treatment yielding reduced secondary tissue damage and enhanced behavioral recovery following severe spinal cord injury. J Neurosurg Spine. 5(4), 343–352 (2006).PubMedGoogle Scholar
  138. 138.
    Bao F, Chen Y, Dekaban GA, Weaver LC. Early anti-inflammatory treatment reduces lipid peroxidation and protein nitration after spinal cord injury in rats. J Neurochem. 88(6), 1335–1344 (2004).PubMedGoogle Scholar
  139. 139.
    Bao F, Omana V, Brown A, Weaver LC. The systemic inflammatory response after spinal cord injury in the rat is decreased by α4β1 integrin blockade. J Neurotrauma. 29(8), 1626–1637 (2012).PubMedPubMedCentralGoogle Scholar
  140. 140.
    Fleming JC, Bao F, Chen Y, Hamilton EF, Relton JK, Weaver LC. Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function. Exp Neurol. 214(2), 147–159 (2008).PubMedGoogle Scholar
  141. 141.
    Plemel JR, Wee Yong V, Stirling DP. Immune modulatory therapies for spinal cord injury—past, present and future. Exp Neurol. 258, 91–104 (2014).PubMedGoogle Scholar
  142. 142.
    Kwon BK, Okon E, Hillyer J, et al. A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma. 28(8), 1545–1588 (2011).PubMedPubMedCentralGoogle Scholar
  143. 143.
    Utagawa A, Bramlett HM, Daniels L, et al. Transient blockage of the CD11d/CD18 integrin reduces contusion volume and macrophage infiltration after traumatic brain injury in rats. Brain Res. 1207, 155–163 (2008).PubMedPubMedCentralGoogle Scholar
  144. 144.
    Van Rooijen N, Hendrikx E. Liposomes for specific depletion of macrophages from organs and tissues. Methods Mol Biol. 605, 189–203 (2010).PubMedGoogle Scholar
  145. 145.
    Iannotti CA, Clark M, Horn KP, Van Rooijen N, Silver J, Steinmetz MP. A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI. Exp Neurol. 230(1), 3–15 (2011).PubMedGoogle Scholar
  146. 146.
    Horn KP, Busch SA, Hawthorne AL, Van Rooijen N, Silver J. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. Journal of Neuroscience. 28(38), 9330–9341 (2008).PubMedGoogle Scholar
  147. 147.
    Wu F, Wei X, Wu Y, et al. Chloroquine promotes the recovery of acute spinal cord injury by inhibiting autophagy-associated inflammation and endoplasmic reticulum stress. J Neurotrauma. (2018).Google Scholar
  148. 148.
    Giulian D, Chen J, Ingeman JE, George JK, Noponen M. The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J Neurosci. 9(12), 4416–4429 (1989).PubMedGoogle Scholar
  149. 149.
    Blight AR. Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage. Neuroscience. 60(1), 263–273 (1994).PubMedGoogle Scholar
  150. 150.
    Gensel JC, Kopper TJ, Zhang B, Orr MB, Bailey WM. Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment. Sci. Rep. 7, 40144 (2017).PubMedPubMedCentralGoogle Scholar
  151. 151.
    Jeong SJ, Cooper JG, Ifergan I, et al. Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice. Neurobiol Dis. 108, 73–82 (2017).PubMedPubMedCentralGoogle Scholar
  152. 152.
    Evans TA, Barkauskas DS, Myers JT, et al. High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp Neurol. 254C, 109–120 (2014).Google Scholar
  153. 153.
    Donnelly DJ, Longbrake EE, Shawler TM, et al. Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. Journal of Neuroscience. 31(27), 9910–9922 (2011).PubMedGoogle Scholar
  154. 154.
    Saxena A, Russo I, Frangogiannis NG. Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. Transl Res. 167(1), 152–166 (2016).PubMedGoogle Scholar
  155. 155.
    Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354(9), 899–910 (2006).PubMedGoogle Scholar
  156. 156.
    Elkins J, Veltkamp R, Montaner J, et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 16(3), 217–226 (2017).PubMedGoogle Scholar
  157. 157.
    Hawthorne AL, Popovich PG. Emerging concepts in myeloid cell biology after spinal cord injury. Neurotherapeutics. 8(2), 252–261 (2011).PubMedPubMedCentralGoogle Scholar
  158. 158.
    Bomstein Y, Marder JB, Vitner K, et al. Features of skin-coincubated macrophages that promote recovery from spinal cord injury. J Neuroimmunol. 142(1–2), 10–16 (2003).PubMedGoogle Scholar
  159. 159.
    Ma S-F, Chen Y-J, Zhang J-X, et al. Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury. Brain Behav Immun. 45, 157–170 (2015).PubMedGoogle Scholar
  160. 160.
    Jones LAT, Lammertse DP, Charlifue SB, et al. A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics. Spinal Cord. 48(11), 798–807 (2010).PubMedGoogle Scholar
  161. 161.
    Knoller N, Auerbach G, Fulga V, et al. Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine. 3(3), 173–181 (2005).PubMedGoogle Scholar
  162. 162.
    Lammertse DP, Jones LAT, Charlifue SB, et al. Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal Cord. 50(9), 661–671 (2012).PubMedGoogle Scholar
  163. 163.
    Lammertse DP. Clinical trials in spinal cord injury: lessons learned on the path to translation. The 2011 International Spinal Cord Society Sir Ludwig Guttmann Lecture. Spinal Cord. 51(1), 2–9 (2013).PubMedGoogle Scholar
  164. 164.
    Kong X, Gao J. Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J. Cell. Mol. Med. 21(5), 941–954 (2017).PubMedGoogle Scholar
  165. 165.
    Cheng Z, Zhu W, Cao K, et al. Anti-inflammatory mechanism of neural stem cell transplantation in spinal cord injury. Int J Mol Sci. 17(9) (2016).Google Scholar
  166. 166.
    Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 3(1), 23–35 (2003).PubMedGoogle Scholar
  167. 167.
    Francos-Quijorna I, Amo-Aparicio J, Martinez-Muriana A, López-Vales R. IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury. Glia. 64(12), 2079–2092 (2016).PubMedGoogle Scholar
  168. 168.
    Lima R, Monteiro S, Lopes JP, et al. Systemic interleukin-4 administration after spinal cord injury modulates inflammation and promotes neuroprotection. Pharmaceuticals (Basel). 10(4) (2017).Google Scholar
  169. 169.
    Coll-Miró M, Francos-Quijorna I, Santos-Nogueira E, et al. Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci USA. (2016).Google Scholar
  170. 170.
    Dooley D, Lemmens E, Vangansewinkel T, et al. Cell-based delivery of interleukin-13 directs alternative activation of macrophages resulting in improved functional outcome after spinal cord injury. Stem Cell Reports. 7(6), 1099–1115 (2016).PubMedPubMedCentralGoogle Scholar
  171. 171.
    Guo Y, Zhang H, Yang J, et al. Granulocyte colony-stimulating factor improves alternative activation of microglia under microenvironment of spinal cord injury. Neuroscience. 238, 1–10 (2013).PubMedGoogle Scholar
  172. 172.
    Dooley D, Lemmens E, Ponsaerts P, Hendrix S. Interleukin-25 is detrimental for recovery after spinal cord injury in mice. J Neuroinflammation. 13(1), 101 (2016).PubMedPubMedCentralGoogle Scholar
  173. 173.
    Guerrero AR, Uchida K, Nakajima H, et al. Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. J Neuroinflammation. 9, 40 (2012).PubMedPubMedCentralGoogle Scholar
  174. 174.
    Mukaino M, Nakamura M, Yamada O, et al. Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation. Exp Neurol. 224(2), 403–414 (2010).PubMedGoogle Scholar
  175. 175.
    Okada S, Nakamura M, Mikami Y, et al. Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res. 76(2), 265–276 (2004).PubMedGoogle Scholar
  176. 176.
    Esposito E, Cuzzocrea S. Anti-TNF therapy in the injured spinal cord. Trends in Pharmacological Sciences. 32(2), 107–115 (2011).PubMedGoogle Scholar
  177. 177.
    Saxena T, Loomis KH, Pai SB, et al. Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury. ACS Nano. 9(2), 1492–1505 (2015).PubMedGoogle Scholar
  178. 178.
    Papa S, Caron I, Erba E, et al. Early modulation of pro-inflammatory microglia by minocycline loaded nanoparticles confers long lasting protection after spinal cord injury. Biomaterials. 75, 13–24 (2016).PubMedGoogle Scholar
  179. 179.
    Francos-Quijorna I, Santos-Nogueira E, Gronert K, et al. Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. Journal of Neuroscience. 37(48), 11731–11743 (2017).PubMedGoogle Scholar
  180. 180.
    Zhang P, Holscher C, Ma X. Therapeutic potential of flavonoids in spinal cord injury. Rev Neurosci. 28(1), 87–101 (2017).PubMedGoogle Scholar
  181. 181.
    Ulndreaj A, Chio JCT, Ahuja CS, Fehlings MG. Modulating the immune response in spinal cord injury. Expert Rev Neurother. 16(10), 1127–1129 (2016).PubMedGoogle Scholar
  182. 182.
    Orr MB, Simkin J, Bailey WM, et al. Compression decreases anatomical and functional recovery and alters inflammation after contusive spinal cord injury. J Neurotrauma. 34(15), 2342–2352 (2017).PubMedPubMedCentralGoogle Scholar
  183. 183.
    Orr MB, Gensel JC. Interactions of primary insult biomechanics and secondary cascades in spinal cord injury: implications for therapy. Neural Regen Res. 12(10), 1618–1619 (2017).PubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  1. 1.Spinal Cord and Brain Injury Research Center, Department of PhysiologyUniversity of Kentucky College of MedicineLexingtonUSA

Personalised recommendations