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

Elsevier BV - Tập 15 Số 3 - Trang 541-553 - 2018
Michael B. Orr1, John C. Gensel1
1Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky College of Medicine, 741 S. Limestone, B463 BBSRB, Lexington, Kentucky, 40536, USA

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Bell, 2010, Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging, Neuron, 68, 409, 10.1016/j.neuron.2010.09.043

Göritz, 2011, A pericyte origin of spinal cord scar tissue, Science, 333, 238, 10.1126/science.1203165

Peppiatt, 2006, Bidirectional control of CNS capillary diameter by pericytes, Nature, 443, 700, 10.1038/nature05193

Oyinbo, 2011, Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade, Acta Neurobiol Exp (Wars), 71, 281, 10.55782/ane-2011-1848

Beck, 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, 10.1093/brain/awp322

Fleming, 2006, The cellular inflammatory response in human spinal cords after injury, Brain, 129, 3249, 10.1093/brain/awl296

Sroga, 2003, Rats and mice exhibit distinct inflammatory reactions after spinal cord injury, J Comp Neurol, 462, 223, 10.1002/cne.10736

Soderblom, 2013, Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury, Journal of Neuroscience, 33, 13882, 10.1523/JNEUROSCI.2524-13.2013

Bruce, 2000, Schwannosis: role of gliosis and proteoglycan in human spinal cord injury, J Neurotrauma, 17, 781, 10.1089/neu.2000.17.781

Buss, 2007, Growth-modulating molecules are associated with invading Schwann cells and not astrocytes in human traumatic spinal cord injury, Brain, 130, 940

Zhang, 2013, Role of endogenous Schwann cells in tissue repair after spinal cord injury, Neural Regen Res, 8, 177

Beattie, 1997, Endogenous repair after spinal cord contusion injuries in the rat, Exp Neurol, 148, 453, 10.1006/exnr.1997.6695

Anderson, 2016, Astrocyte scar formation aids central nervous system axon regeneration, Nature, 532, 195, 10.1038/nature17623

Burda, 2014, Reactive gliosis and the multicellular response to CNS damage and disease, Neuron, 81, 229, 10.1016/j.neuron.2013.12.034

Zhu, 2014, Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury, Neurobiol Dis, 74C, 114

Zamanian, 2012, Genomic analysis of reactive astrogliosis, Journal of Neuroscience, 32, 6391, 10.1523/JNEUROSCI.6221-11.2012

David, 1981, Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats, Science, 214, 931, 10.1126/science.6171034

Abnet, 1991, Interactions between meningeal cells and astrocytes in vivo and in vitro, Brain Res. Dev. Brain Res, 59, 187, 10.1016/0165-3806(91)90099-5

Bundesen, 2003, Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats, Journal of Neuroscience, 23, 7789, 10.1523/JNEUROSCI.23-21-07789.2003

Shearer, 2001, The astrocyte/meningeal cell interface—a barrier to successful nerve regeneration?, Cell Tissue Res, 305, 267, 10.1007/s004410100384

Kimura-Kuroda, 2010, An in vitro model of the inhibition of axon growth in the lesion scar formed after central nervous system injury, Mol. Cell. Neurosci, 43, 177, 10.1016/j.mcn.2009.10.008

Kawano, 2012, Role of the lesion scar in the response to damage and repair of the central nervous system, Cell Tissue Res, 349, 169, 10.1007/s00441-012-1336-5

Bradbury, 2002, Chondroitinase ABC promotes functional recovery after spinal cord injury, Nature, 416, 636, 10.1038/416636a

Tang, 2003, 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, 427, 10.1002/jnr.10523

McKeon, 1999, The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar, Journal of Neuroscience, 19, 10778, 10.1523/JNEUROSCI.19-24-10778.1999

Zhu, 2015, Fibronectin matrix assembly after spinal cord injury, J Neurotrauma, 32, 1158, 10.1089/neu.2014.3703

Schreiber, 2013, Extracellular matrix alterations, accelerated leukocyte infiltration and enhanced axonal sprouting after spinal cord hemisection in tenascin-C-deficient mice, Acta Histochem, 115, 865, 10.1016/j.acthis.2013.04.009

Weidner, 1999, Elimination of basal lamina and the collagen “scar” after spinal cord injury fails to augment corticospinal tract regeneration, Exp Neurol, 160, 40, 10.1006/exnr.1999.7200

Klapka, 2005, 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, 3047, 10.1111/j.1460-9568.2005.04495.x

Loy, 2002, Temporal progression of angiogenesis and basal lamina deposition after contusive spinal cord injury in the adult rat, J Comp Neurol, 445, 308, 10.1002/cne.10168

Klapka, 2006, Collagen matrix in spinal cord injury, J Neurotrauma, 23, 422, 10.1089/neu.2006.23.422

Ruschel, 2015, Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury, Science, 348, 347, 10.1126/science.aaa2958

McKeon, 1991, 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, 3398, 10.1523/JNEUROSCI.11-11-03398.1991

Stichel, 1999, Basal membrane-depleted scar in lesioned CNS: characteristics and relationships with regenerating axons, Neuroscience, 93, 321, 10.1016/S0306-4522(99)00112-8

Donnelly, 2008, Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury, Exp Neurol, 209, 378, 10.1016/j.expneurol.2007.06.009

Mawhinney, 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, 10.1097/NEN.0b013e3182479b41

Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, Journal of Neuroscience, 29, 13435, 10.1523/JNEUROSCI.3257-09.2009

Carlson, 1998, Acute inflammatory response in spinal cord following impact injury, Exp Neurol, 151, 77, 10.1006/exnr.1998.6785

Taoka, 1997, Role of neutrophils in spinal cord injury in the rat, Neuroscience, 79, 1177, 10.1016/S0306-4522(97)00011-0

Popovich, 1999, Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury, Exp Neurol, 158, 351, 10.1006/exnr.1999.7118

Wang, 2013, Microglia/macrophage polarization dynamics in white matter after traumatic brain injury, J Cereb Blood Flow Metab, 33, 1864, 10.1038/jcbfm.2013.146

Fitch, 1999, 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, 8182, 10.1523/JNEUROSCI.19-19-08182.1999

Soderblom, 2015, 3D imaging of axons in transparent spinal cords from rodents and nonhuman primates, eNeuro, 2, 10.1523/ENEURO.0001-15.2015

Decimo, 2011, Nestin- and doublecortin-positive cells reside in adult spinal cord meninges and participate in injury-induced parenchymal reaction, STEM CELLS, 29, 2062, 10.1002/stem.766

Zhang, 2015, Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury, J Neuroinflammation, 12, 218, 10.1186/s12974-015-0440-3

Bloom, 2014, Non-mammalian model systems for studying neuro-immune interactions after spinal cord injury, Exp Neurol, 258, 130, 10.1016/j.expneurol.2013.12.023

Goldshmit, 2012, Fgf-dependent glial cell bridges facilitate spinal cord regeneration in zebrafish, Journal of Neuroscience, 32, 7477, 10.1523/JNEUROSCI.0758-12.2012

Zukor, 2011, Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts, Neural Dev, 6, 1, 10.1186/1749-8104-6-1

Logan, 1994, Effects of transforming growth factor beta 1 on scar production in the injured central nervous system of the rat, Eur J Neurosci, 6, 355, 10.1111/j.1460-9568.1994.tb00278.x

East, 2009, A versatile 3D culture model facilitates monitoring of astrocytes undergoing reactive gliosis, J Tissue Eng Regen Med, 3, 634, 10.1002/term.209

Renault-Mihara, 2017, Regulation of RhoA by STAT3 coordinates glial scar formation, J Cell Biol, 216, 2533, 10.1083/jcb.201610102

Wanner, 2013, 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, 12870, 10.1523/JNEUROSCI.2121-13.2013

Faulkner, 2004, Reactive astrocytes protect tissue and preserve function after spinal cord injury, J Neurosci, 24, 2143, 10.1523/JNEUROSCI.3547-03.2004

Bott, 2010, The effect of matrix characteristics on fibroblast proliferation in 3D gels, Biomaterials, 31, 8454, 10.1016/j.biomaterials.2010.07.046

Harris, 2017, Nerve guidance by a decellularized fibroblast extracellular matrix, Matrix Biol, 60-61, 176, 10.1016/j.matbio.2016.08.011

Franze, 2013, Mechanics in neuronal development and repair, Annu Rev Biomed Eng, 15, 227, 10.1146/annurev-bioeng-071811-150045

Tremble, 1994, The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts, Mol. Biol. Cell, 5, 439, 10.1091/mbc.5.4.439

Trebaul, 2007, Regulation of fibroblast migration by tenascin-C, Biochem. Soc. Trans, 35, 695, 10.1042/BST0350695

Kalembeyi, 2003, Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1, Int. J. Cancer, 105, 53, 10.1002/ijc.11037

Ogier, 2006, Matrix metalloproteinase-2 (MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins, Glia, 54, 272, 10.1002/glia.20349

Goussev, 2003, Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing, J. Neurosurg, 99, 188

Tezel, 2001, In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head, Glia, 34, 178, 10.1002/glia.1052

Takenaga, 2006, Role of intracellular S100A4 for migration of rat astrocytes, Glia, 53, 313, 10.1002/glia.20284

Yu, 2008, Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury, J Neurotrauma, 25, 184, 10.1089/neu.2007.0438

Hsu, 2006, Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury, Journal of Neuroscience, 26, 9841, 10.1523/JNEUROSCI.1993-06.2006

Zhang, 2011, 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, 15894, 10.1523/JNEUROSCI.3943-11.2011

Shechter, 2011, The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair, PLoS ONE, 6, 10.1371/journal.pone.0027969

Rolls, 2008, Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation, PLoS Med, 5, e171, 10.1371/journal.pmed.0050171

Tasdemir-Yilmaz, 2014, Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons, Genes Dev, 28, 20, 10.1101/gad.229518.113

Clark, 1993, Growth cone guidance and neuron morphology on micropatterned laminin surfaces, Journal of Cell Science, 105, 203, 10.1242/jcs.105.1.203

Chung, 2013, Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways, Nature, 504, 394, 10.1038/nature12776

Bush, 1999, Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice, Neuron, 23, 297, 10.1016/S0896-6273(00)80781-3

Alilain, 2011, Functional regeneration of respiratory pathways after spinal cord injury, Nature, 475, 196, 10.1038/nature10199

Manwaring, 2004, Contact guidance induced organization of extracellular matrix, Biomaterials, 25, 3631, 10.1016/j.biomaterials.2003.10.043

Gonzalez-Perez, 2013, Extracellular matrix components in peripheral nerve regeneration, Int. Rev. Neurobiol, 108, 257, 10.1016/B978-0-12-410499-0.00010-1

Shen, 2014, Scar-modulating treatments for central nervous system injury, Neurosci Bull, 30, 967, 10.1007/s12264-013-1456-2

O'Shea, 2017, Cell biology of spinal cord injury and repair, J Clin Invest, 127, 3259, 10.1172/JCI90608

Buss, 2004, Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord, Brain, 127, 34, 10.1093/brain/awh001

Buss, 2009, NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury, BMC Neurol, 9, 32, 10.1186/1471-2377-9-32

Norenberg, 2004, The pathology of human spinal cord injury: defining the problems, J Neurotrauma, 21, 429, 10.1089/089771504323004575

Guest, 2005, Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury, Exp Neurol, 192, 384, 10.1016/j.expneurol.2004.11.033

Jones, 2003, The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury, Exp Neurol, 182, 399, 10.1016/S0014-4886(03)00087-6

Shen, 2009, PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration, Science, 326, 592, 10.1126/science.1178310

McKillop, 2013, Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury, Glia, 61, 164, 10.1002/glia.22424

Takeuchi, 2013, Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury, Nat Commun, 4, 10.1038/ncomms3740

Oudega, 2012, Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury, Exp Neurol, 237, 170, 10.1016/j.expneurol.2012.06.006

Grimpe, 2004, 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, 1393, 10.1523/JNEUROSCI.4986-03.2004

Bradbury, 2011, Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury, Brain Res. Bull, 84, 306, 10.1016/j.brainresbull.2010.06.015

Carter, 2008, 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, 14107, 10.1523/JNEUROSCI.2217-08.2008

Bartus, 2014, 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, 4822, 10.1523/JNEUROSCI.4369-13.2014

Xu, 2018, Sox9 knockout mice have improved recovery following stroke, Exp Neurol, 303, 59, 10.1016/j.expneurol.2018.02.001

Didangelos, 2014, Regulation of IL-10 by chondroitinase ABC promotes a distinct Immune response following spinal cord injury, Journal of Neuroscience, 34, 16424, 10.1523/JNEUROSCI.2927-14.2014

Shechter, 2009, Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice, PLoS Med, 6, 10.1371/journal.pmed.1000113

Gensel, 2012, Achieving CNS axon regeneration by manipulating convergent neuro-immune signaling, Cell Tissue Res, 349, 201, 10.1007/s00441-012-1425-5

Gensel, 2011, 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, 505, 10.1517/14728222.2011.553605

Hesp, 2017, Proliferating NG2 cell-dependent angiogenesis and scar formation alter axon growth and functional recovery after spinal cord injury in mice, Journal of Neuroscience

Zhao, 2017, Mechanisms responsible for the inhibitory effects of epothilone B on scar formation after spinal cord injury, Neural Regen Res, 12, 478, 10.4103/1673-5374.202921

Ruschel, 2017, Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury, Exp Neurol

Sandner, 2018, Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats, Exp Neurol, 10.1016/j.expneurol.2018.01.018

Hao, 2017, Mechanisms underlying the promotion of functional recovery by deferoxamine after spinal cord injury in rats, Neural Regen Res, 12, 959, 10.4103/1673-5374.208591

Falnikar, 2015, Therapeutically targeting astrocytes with stem and progenitor cell transplantation following traumatic spinal cord injury, Brain Res, 1619, 91, 10.1016/j.brainres.2014.09.037

Hill, 2004, 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, 289, 10.1016/j.expneurol.2004.05.043

Xiao, 2016, One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients, Sci China Life Sci, 59, 647, 10.1007/s11427-016-5080-z

Zhao, 2017, Clinical study of NeuroRegen scaffold combined with human mesenchymal stem cells for the repair of chronic complete spinal cord injury, Cell Transplant, 26, 891, 10.3727/096368917X695038

Haggerty, 2017, Extracellular matrix components as therapeutics for spinal cord injury, Neurosci Lett, 652, 50, 10.1016/j.neulet.2016.09.053

Kigerl, 2009, Toll-like receptors in spinal cord injury, Curr. Top. Microbiol. Immunol, 336, 121

Kigerl, 2014, Pattern recognition receptors and central nervous system repair, Exp Neurol, 258, 5, 10.1016/j.expneurol.2014.01.001

Sofroniew, 2009, Molecular dissection of reactive astrogliosis and glial scar formation, Trends Neurosci, 32, 638, 10.1016/j.tins.2009.08.002

David, 2011, Repertoire of microglial and macrophage responses after spinal cord injury, Nat Rev Neurosci, 12, 388, 10.1038/nrn3053

Gensel, 2015, Macrophage activation and its role in repair and pathology after spinal cord injury, Brain Res, 1619, 1, 10.1016/j.brainres.2014.12.045

Mabon, 2000, 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, 52, 10.1006/exnr.2000.7488

Yang, 2004, 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, 966, 10.1097/00007632-200405010-00004

Kigerl, 2006, Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury, J Comp Neurol, 494, 578, 10.1002/cne.20827

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.

de Castro, 2004, Evidence that infiltrating neutrophils do not release reactive oxygen species in the site of spinal cord injury, Exp Neurol, 190, 414, 10.1016/j.expneurol.2004.05.046

Kubota, 2012, Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury, Spine, 37, 1363, 10.1097/BRS.0b013e31824b9e77

Prüss, 2011, Non-resolving aspects of acute inflammation after spinal cord injury (SCI): indices and resolution plateau, Brain Pathology (Zurich, Switzerland), 21, 652, 10.1111/j.1750-3639.2011.00488.x

Martinez, 2009, Alternative activation of macrophages: an immunologic functional perspective, Annu. Rev. Immunol, 27, 451, 10.1146/annurev.immunol.021908.132532

Gensel, 2009, Macrophages promote axon regeneration with concurrent neurotoxicity, Journal of Neuroscience, 29, 3956, 10.1523/JNEUROSCI.3992-08.2009

Greenhalgh, 2016, Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease, Brain Behav Immun, 10.1016/j.bbi.2016.04.013

Ren, 2013, Managing inflammation after spinal cord injury through manipulation of macrophage function, Neural Plasticity, 2013, 10.1155/2013/945034

Benowitz, 2011, Inflammation and axon regeneration, Curr. Opin. Neurol, 24, 577, 10.1097/WCO.0b013e32834c208d

Huang, 2014, Identification of distinct monocyte phenotypes and correlation with circulating cytokine profiles in acute response to spinal cord injury: a pilot study, PM&R, 6, 332, 10.1016/j.pmrj.2013.10.006

Kigerl, 2006, Drug evaluation: ProCord—a potential cell-based therapy for spinal cord injury, IDrugs, 9, 354

Rapalino, 1998, Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats, Nat Med, 4, 814, 10.1038/nm0798-814

Rabchevsky, 1997, Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth, J Neurosci Res, 47, 34, 10.1002/(SICI)1097-4547(19970101)47:1<34::AID-JNR4>3.0.CO;2-G

Bracken, 1990, 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, 1405, 10.1056/NEJM199005173222001

Bowers, 2016, Methylprednisolone for acute spinal cord injury: an increasingly philosophical debate, Neural Regen Res, 11, 882, 10.4103/1673-5374.184450

Geremia, 2012, CD11d antibody treatment improves recovery in spinal cord-injured mice, J Neurotrauma, 29, 539, 10.1089/neu.2011.1976

Bao, 2011, CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury, Exp Neurol, 231, 272, 10.1016/j.expneurol.2011.07.001

Shultz, 2013, Treatment with an anti-CD11d integrin antibody reduces neuroinflammation and improves outcome in a rat model of repeated concussion, J Neuroinflammation, 10, 26, 10.1186/1742-2094-10-26

Bao, 2012, A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats, J Neurotrauma, 29, 2375, 10.1089/neu.2012.2408

Saville, 2004, A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment, J Neuroimmunol, 156, 42, 10.1016/j.jneuroim.2004.07.002

Bao, 2005, Anti-CD11d antibody treatment reduces free radical formation and cell death in the injured spinal cord of rats, J Neurochem, 94, 1361, 10.1111/j.1471-4159.2005.03280.x

Oatway, 2005, 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, 637, 10.1523/JNEUROSCI.3960-04.2005

Gris, 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, 10.1523/JNEUROSCI.5343-03.2004

Ditor, 2006, 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, 343, 10.3171/spi.2006.5.4.343

Bao, 2004, Early anti-inflammatory treatment reduces lipid peroxidation and protein nitration after spinal cord injury in rats, J Neurochem, 88, 1335, 10.1046/j.1471-4159.2003.02240.x

Bao, 2012, The systemic inflammatory response after spinal cord injury in the rat is decreased by α4β1 integrin blockade, J Neurotrauma, 29, 1626, 10.1089/neu.2011.2190

Fleming, 2008, Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function, Exp Neurol, 214, 147, 10.1016/j.expneurol.2008.04.024

Plemel, 2014, Immune modulatory therapies for spinal cord injury—past, present and future, Exp Neurol, 258, 91, 10.1016/j.expneurol.2014.01.025

Kwon, 2011, A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury, J Neurotrauma, 28, 1545, 10.1089/neu.2009.1149

Utagawa, 2008, Transient blockage of the CD11d/CD18 integrin reduces contusion volume and macrophage infiltration after traumatic brain injury in rats, Brain Res, 1207, 155, 10.1016/j.brainres.2008.02.057

Van Rooijen, 2010, Liposomes for specific depletion of macrophages from organs and tissues, Methods Mol Biol, 605, 189, 10.1007/978-1-60327-360-2_13

Iannotti, 2011, A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI, Exp Neurol, 230, 3, 10.1016/j.expneurol.2010.03.010

Horn, 2008, Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions, Journal of Neuroscience, 28, 9330, 10.1523/JNEUROSCI.2488-08.2008

Wu, 2018, Chloroquine promotes the recovery of acute spinal cord injury by inhibiting autophagy-associated inflammation and endoplasmic reticulum stress, J Neurotrauma, 10.1089/neu.2017.5414

Giulian, 1989, The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain, J Neurosci, 9, 4416, 10.1523/JNEUROSCI.09-12-04416.1989

Blight, 1994, Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage, Neuroscience, 60, 263, 10.1016/0306-4522(94)90220-8

Gensel, 2017, Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment, Sci. Rep, 7, 10.1038/srep40144

Jeong, 2017, Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice, Neurobiol Dis, 108, 73, 10.1016/j.nbd.2017.08.006

Evans, 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, 254C, 109, 10.1016/j.expneurol.2014.01.013

Donnelly, 2011, Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages, Journal of Neuroscience, 31, 9910, 10.1523/JNEUROSCI.2114-11.2011

Saxena, 2016, Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges, Transl Res, 167, 152, 10.1016/j.trsl.2015.07.002

Polman, 2006, A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis, N. Engl. J. Med, 354, 899, 10.1056/NEJMoa044397

Elkins, 2017, Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial, Lancet Neurol, 16, 217, 10.1016/S1474-4422(16)30357-X

Hawthorne, 2011, Emerging concepts in myeloid cell biology after spinal cord injury, Neurotherapeutics, 8, 252, 10.1007/s13311-011-0032-6

Bomstein, 2003, Features of skin-coincubated macrophages that promote recovery from spinal cord injury, J Neuroimmunol, 142, 10, 10.1016/S0165-5728(03)00260-1

Ma, 2015, Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury, Brain Behav Immun, 45, 157, 10.1016/j.bbi.2014.11.007

Jones, 2010, A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics, Spinal Cord, 48, 798, 10.1038/sc.2010.29

Knoller, 2005, Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results, J Neurosurg Spine, 3, 173, 10.3171/spi.2005.3.3.0173

Lammertse, 2012, Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial, Spinal Cord, 50, 661, 10.1038/sc.2012.39

Lammertse, 2013, 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, 2, 10.1038/sc.2012.137

Kong, 2017, Macrophage polarization: a key event in the secondary phase of acute spinal cord injury, J. Cell. Mol. Med, 21, 941, 10.1111/jcmm.13034

Cheng, 2016, Anti-inflammatory mechanism of neural stem cell transplantation in spinal cord injury, Int J Mol Sci, 17, 10.3390/ijms17091380

Gordon, 2003, Alternative activation of macrophages, Nat Rev Immunol, 3, 23, 10.1038/nri978

Francos-Quijorna, 2016, IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury, Glia, 64, 2079, 10.1002/glia.23041

Lima, 2017, Systemic interleukin-4 administration after spinal cord injury modulates inflammation and promotes neuroprotection, Pharmaceuticals (Basel), 10, 10.3390/ph10040083

Coll-Miró, 2016, Beneficial effects of IL-37 after spinal cord injury in mice, Proc Natl Acad Sci USA, 10.1073/pnas.1523212113

Dooley, 2016, Cell-based delivery of interleukin-13 directs alternative activation of macrophages resulting in improved functional outcome after spinal cord injury, Stem Cell Reports, 7, 1099, 10.1016/j.stemcr.2016.11.005

Guo, 2013, Granulocyte colony-stimulating factor improves alternative activation of microglia under microenvironment of spinal cord injury, Neuroscience, 238, 1, 10.1016/j.neuroscience.2013.01.047

Dooley, 2016, Interleukin-25 is detrimental for recovery after spinal cord injury in mice, J Neuroinflammation, 13, 101, 10.1186/s12974-016-0566-y

Guerrero, 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 Neuroinflammation, 9, 40, 10.1186/1742-2094-9-40

Mukaino, 2010, Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation, Exp Neurol, 224, 403, 10.1016/j.expneurol.2010.04.020

Okada, 2004, Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury, J Neurosci Res, 76, 265, 10.1002/jnr.20044

Esposito, 2011, Anti-TNF therapy in the injured spinal cord, Trends in Pharmacological Sciences, 32, 107, 10.1016/j.tips.2010.11.009

Saxena, 2015, Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury, ACS Nano, 9, 1492, 10.1021/nn505980z

Papa, 2016, Early modulation of pro-inflammatory microglia by minocycline loaded nanoparticles confers long lasting protection after spinal cord injury, Biomaterials, 75, 13, 10.1016/j.biomaterials.2015.10.015

Francos-Quijorna, 2017, Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury, Journal of Neuroscience, 37, 11731, 10.1523/JNEUROSCI.1395-17.2017

Zhang, 2017, Therapeutic potential of flavonoids in spinal cord injury, Rev Neurosci, 28, 87, 10.1515/revneuro-2016-0053

Ulndreaj, 2016, Modulating the immune response in spinal cord injury, Expert Rev Neurother, 16, 1127, 10.1080/14737175.2016.1207532

Orr, 2017, Compression decreases anatomical and functional recovery and alters inflammation after contusive spinal cord injury, J Neurotrauma, 34, 2342, 10.1089/neu.2016.4915

Orr, 2017, Interactions of primary insult biomechanics and secondary cascades in spinal cord injury: implications for therapy, Neural Regen Res, 12, 1618, 10.4103/1673-5374.217332