Neuroinflammation: the devil is in the details

Journal of Neurochemistry

Volumn 139, Issue , 2016, Pages 136-153

  DiSabato, Damon J ^a   Quan, Ning ^a   Godbout, Jonathan P ^a  

^a OHIO STATE UNIVERSITY   (United States)

Author keywords

astrocytes; lipopolysaccharide; microglia; neuroinflammation; sickness behavior

Indexed keywords

CYTOKINE; INTERLEUKIN 10; INTERLEUKIN 13; INTERLEUKIN 1BETA; INTERLEUKIN 4;

AGING; ARTICLE; CELL ACTIVATION; CENTRAL NERVOUS SYSTEM; DISEASE ASSOCIATION; EVIDENCE BASED MEDICINE; HUMAN; ILLNESS BEHAVIOR; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOREACTIVITY; MEMORY; MENTAL STRESS; MICROGLIA; NERVOUS SYSTEM INFLAMMATION; NERVOUS SYSTEM INJURY; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; SPINAL CORD INJURY; TISSUE REGENERATION; TISSUE REPAIR; TRAUMATIC BRAIN INJURY; ANIMAL; BRAIN; DEGENERATIVE DISEASE; INFLAMMATION; METABOLISM; PATHOLOGY; SPINAL CORD;

AGING; ANIMALS; BRAIN; HUMANS; INFLAMMATION; MICROGLIA; NEURODEGENERATIVE DISEASES; SPINAL CORD;

EID: 84964928591     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/jnc.13607     Document Type: Article

References (201)

1. Abdul-Muneer P. M., Schuetz H., Wang F., Skotak M., Jones J., Gorantla S., Zimmerman M. C., Chandra N. and Haorah J. (2013) Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Free Radic. Biol. Med. 60, 282–291.
2. Abraham J. and Johnson R. W. (2008) Central inhibition of interleukin-1beta ameliorates sickness behavior in aged mice. Brain Behav. Immun. 29, 614–621.
3. Abraham J. and Johnson R. W. (2009) Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res. 12, 445–453.
4. Abraham J., Jang S., Godbout J. P., Chen J., Kelley K. W., Dantzer R. and Johnson R. W. (2008) Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120. Neurobiol. Aging 29, 614–621.
5. Ajami B., Bennett J. L., Krieger C., Tetzlaff W. and Rossi F. M. (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543.
6. Alliot F., Godin I. and Pessac B. (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152.
7. Andonova M., Goundasheva D., Georgiev P. and Ivanov V. (1998) Effects of indomethacin on lipopolysaccharide-induced plasma PGE2 concentrations and clinical pathological disorders in experimental endotoxemia. Vet. Hum. Toxicol. 40, 14–18.
8. Ankeny D. P., Lucin K. M., Sanders V. M., McGaughy V. M. and Popovich P. G. (2006) Spinal cord injury triggers systemic autoimmunity: evidence for chronic B lymphocyte activation and lupus-like autoantibody synthesis. J. Neurochem. 99, 1073–1087.
9. Aungst S. L., Kabadi S. V., Thompson S. M., Stoica B. A. and Faden A. I. (2014) Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. J. Cereb. Blood Flow Metab. 34, 1223–1232.
10. Baalman K., Marin M. A., Ho T. S., Godoy M., Cherian L., Robertson C. and Rasband M. N. (2015) Axon initial segment-associated microglia. J. Neurosci. 35, 2283–2292.
11. Bachstetter A. D., Xing B., de Almeida L., Dimayuga E. R., Watterson D. M. and Van Eldik L. J. (2011) Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J. Neuroinflammation 8, 79.
12. Bachstetter A. D., Rowe R. K., Kaneko M., Goulding D., Lifshitz J. and Van Eldik L. J. (2013) The p38alpha MAPK regulates microglial responsiveness to diffuse traumatic brain injury. J. Neurosci. 33, 6143–6153.
13. Bao F., Chen Y., Dekaban G. A. and Weaver L. C. (2004) Early anti-inflammatory treatment reduces lipid peroxidation and protein nitration after spinal cord injury in rats. J. Neurochem. 88, 1335–1344.
14. Bao F., Chen Y., Schneider K. A. and Weaver L. C. (2008) An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury. Exp. Neurol. 214, 160–167.
15. Barrette B., Hebert M. A., Filali M., Lafortune K., Vallieres N., Gowing G., Julien J. P. and Lacroix S. (2008) Requirement of myeloid cells for axon regeneration. J. Neurosci. 28, 9363–9376.
16. Barrientos R. M., Higgins E. A., Biedenkapp J. C., Sprunger D. B., Wright-Hardesty K. J., Watkins L. R., Rudy J. W. and Maier S. F. (2006) Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol. Aging 27, 723–732.
17. Barrientos R. M., Frank M. G., Hein A. M., Higgins E. A., Watkins L. R., Rudy J. W. and Maier S. F. (2009a) Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection. Brain Behav. Immun. 23, 46–54.
18. Barrientos R. M., Watkins L. R., Rudy J. W. and Maier S. F. (2009b) Characterization of the sickness response in young and aging rats following E. coli infection. Brain Behav. Immun. 23, 450–454.
19. Bastien D., Bellver Landete V., Lessard M., Vallieres N., Champagne M., Takashima A., Tremblay M. E., Doyon Y. and Lacroix S. (2015) IL-1alpha gene deletion protects oligodendrocytes after spinal cord injury through upregulation of the survival factor Tox3. J. Neurosci. 35, 10715–10730.
20. Baughman V. L., Hoffman W. E., Miletich D. J., Albrecht R. F. and Thomas C. (1988) Neurologic outcome in rats following incomplete cerebral ischemia during halothane, isoflurane, or N2O. Anesthesiology 69, 192–198.
21. Baum A., Cohen L. and Hall M. (1993) Control and intrusive memories as possible determinants of chronic stress. Psychosom. Med. 55, 274–286.
22. Berg B. M., Godbout J. P., Kelley K. W. and Johnson R. W. (2004) Alpha-tocopherol attenuates lipopolysaccharide-induced sickness behavior in mice. Brain Behav. Immun. 18, 149–157.
23. Biswas S. K. and Lopez-Collazo E. (2009) Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487.
24. Blixt J., Svensson M., Gunnarson E. and Wanecek M. (2015) Aquaporins and blood-brain barrier permeability in early edema development after traumatic brain injury. Brain Res. 1611, 18–28.
25. Bluthe R. M., Laye S., Michaud B., Combe C., Dantzer R. and Parnet P. (2000) Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur. J. Neuorsci. 12, 4447–4456.
26. Borowski T., Kokkinidis L., Merali Z. and Anisman H. (1998) Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia. NeuroReport 9, 3797–3802.
27. Bruttger J., Karram K., Wortge S. et al. (2015) Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106.
28. Bucciantini M., Giannoni E., Chiti F. et al. (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511.
29. Buchanan J. B., Sparkman N. L., Chen J. and Johnson R. W. (2008) Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 33, 755–765.
30. Caswell L. W., Vitaliano P. P., Croyle K. L., Scanlan J. M., Zhang J. and Daruwala A. (2003) Negative associations of chronic stress and cognitive performance in older adult spouse caregivers. Exp. Aging Res. 29, 303–318.
31. Chen J., Buchanan J. B., Sparkman N. L., Godbout J. P., Freund G. G. and Johnson R. W. (2008) Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav. Immun. 22, 301–311.
32. Chen Z., Jalabi W., Shpargel K. B. et al. (2012) Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J. Neurosci. 32, 11706–11715.
33. Chen Q., Tarr A. J., Liu X., Wang Y., Reed N. S., Demarsh C. P., Sheridan J. F. and Quan N. (2013) Controlled progressive innate immune stimulation regimen prevents the induction of sickness behavior in the open field test. J. Inflamm. Res. 6, 91–98.
34. Ching S., Zhang H., Belevych N., He L., Lai W., Pu X. A., Jaeger L. B., Chen Q. and Quan N. (2007) Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J. Neurosci. 27, 10476–10486.
35. Choi J. H., Lee C. H., Hwang I. K., Won M. H., Seong J. K., Yoon Y. S., Lee H. S. and Lee I. S. (2007) Age-related changes in ionized calcium-binding adapter molecule 1 immunoreactivity and protein level in the gerbil hippocampal CA1 region. J. Vet. Med. Sci. 69, 1131–1136.
36. Chung H. Y., Cesari M., Anton S., Marzetti E., Giovannini S., Seo A. Y., Carter C., Yu B. P. and Leeuwenburgh C. (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev. 8, 18–30.
37. Corona A. W., Norden D. M., Skendelas J. P., Huang Y., O'Connor J. C., Lawson M., Dantzer R., Kelley K. W. and Godbout J. P. (2013) Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)-deficient mice. Brain Behav. Immun. 31, 134–142.
38. Corps K. N., Roth T. L. and McGavern D. B. (2015) Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol. 72, 355–362.
39. Dantzer R., O'Connor J. C., Freund G. G., Johnson R. W. and Kelley K. W. (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56.
40. Davalos D., Grutzendler J., Yang G., Kim J. V., Zuo Y., Jung S., Littman D. R., Dustin M. L. and Gan W. B. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758.
41. David S. and Kroner A. (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat. Rev. Neurosci. 12, 388–399.
42. David S., Greenhalgh A. D. and Lopez-Vales R. (2012) Role of phospholipase A2s and lipid mediators in secondary damage after spinal cord injury. Cell Tissue Res. 349, 249–267.
43. Derecki N. C., Cardani A. N., Yang C. H., Quinnies K. M., Crihfield A., Lynch K. R. and Kipnis J. (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080.
44. Dunn A. J., Swiergiel A. H., Zhang H. and Quan N. (2006) Reduced ingestion of sweetened milk induced by interleukin-1 and lipopolysaccharide is associated with induction of cyclooxygenase-2 in brain endothelia. NeuroImmunoModulation 13, 96–104.
45. Elmariah S. B., Oh E. J., Hughes E. G. and Balice-Gordon R. J. (2005) Astrocytes regulate inhibitory synapse formation via Trk-mediated modulation of postsynaptic GABAA receptors. J. Neurosci. 25, 3638–3650.
46. Elmore M. R., Najafi A. R., Koike M. A. et al. (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397.
47. Fenn A. M., Henry C. J., Huang Y., Dugan A. and Godbout J. P. (2012) Lipopolysaccharide-induced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav. Immun. 26, 766–777.
48. Fenn A. M., Gensel J. C., Huang Y., Popovich P. G., Lifshitz J. and Godbout J. P. (2014) Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol. Psychiatry 76, 575–584.
49. Fenn A. M., Skendelas J. P., Moussa D. N., Muccigrosso M. M., Popovich P. G., Lifshitz J., Eiferman D. S. and Godbout J. P. (2015) Methylene blue attenuates traumatic brain injury-associated neuroinflammation and acute depressive-like behavior in mice. J. Neurotrauma 32, 127–138.
50. Ferguson A. R., Christensen R. N., Gensel J. C., Miller B. A., Sun F., Beattie E. C., Bresnahan J. C. and Beattie M. S. (2008) Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J. Neurosci. 28, 11391–11400.
51. Fleming J. C., Norenberg M. D., Ramsay D. A., Dekaban G. A., Marcillo A. E., Saenz A. D., Pasquale-Styles M., Dietrich W. D. and Weaver L. C. (2006) The cellular inflammatory response in human spinal cords after injury. Brain 129, 3249–3269.
52. Frank M. G., Barrientos R. M., Biedenkapp J. C., Rudy J. W., Watkins L. R. and Maier S. F. (2006) mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol. Aging 27, 717–722.
53. Frank M. G., Baratta M. V., Sprunger D. B., Watkins L. R. and Maier S. F. (2007) Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav. Immun. 21, 47–59.
54. Freudenthal R., Boccia M. M., Acosta G. B., Blake M. G., Merlo E., Baratti C. M. and Romano A. (2005) NF-kappaB transcription factor is required for inhibitory avoidance long-term memory in mice. Eur. J. Neurosci. 21, 2845–2852.
55. Gebara E., Sultan S., Kocher-Braissant J. and Toni N. (2013) Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging. Front. Neurosci. 7, 145.
56. Genovese T., Mazzon E., Crisafulli C., Di Paola R., Muia C., Esposito E., Bramanti P. and Cuzzocrea S. (2008) TNF-alpha blockage in a mouse model of SCI: evidence for improved outcome. Shock 29, 32–41.
57. Gensel J. C., Nakamura S., Guan Z., van Rooijen N., Ankeny D. P. and Popovich P. G. (2009) Macrophages promote axon regeneration with concurrent neurotoxicity. J. Neurosci. 29, 3956–3968.
58. Gentleman S. M., Leclercq P. D., Moyes L., Graham D. I., Smith C., Griffin W. S. and Nicoll J. A. (2004) Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci. Int. 146, 97–104.
59. Ginhoux F., Greter M., Leboeuf M. et al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845.
60. Godbout J. P., Chen J., Abraham J., Richwine A. F., Berg B. M., Kelley K. W. and Johnson R. W. (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 19, 1329–1331.
61. Godbout J. P., Moreau M., Lestage J. et al. (2008) Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, 2341–2351.
62. Gold R., Linington C. and Lassmann H. (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971.
63. Goldman D., Song X., Kitai R., Casadevall A., Zhao M. L. and Lee S. C. (2001) Cryptococcus neoformans induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta in human microglia: role of specific antibody and soluble capsular polysaccharide. Infect. Immun. 69, 1808–1815.
64. Goshen I. and Yirmiya R. (2009) Interleukin-1 (IL-1): a central regulator of stress responses. Front. Neuroendocrinol. 30, 30–45.
65. Griffin R., Nally R., Nolan Y., McCartney Y., Linden J. and Lynch M. A. (2006) The age-related attenuation in long-term potentiation is associated with microglial activation. J. Neurochem. 99, 1263–1272.
66. Gris D., Marsh D. R., Oatway M. A., Chen Y., Hamilton E. F., Dekaban G. A. and Weaver L. C. (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.
67. Gyoneva S. and Traynelis S. F. (2013) Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors. J. Biol. Chem. 288, 15291–15302.
68. Haber M., Abdel Baki S. G., Grin'kina N. M., Irizarry R., Ershova A., Orsi S., Grill R. J., Dash P. and Bergold P. J. (2013) Minocycline plus N-acetylcysteine synergize to modulate inflammation and prevent cognitive and memory deficits in a rat model of mild traumatic brain injury. Exp. Neurol. 249, 169–177.
69. Hansen M. K., O'Connor K. A., Goehler L. E., Watkins L. R. and Maier S. F. (2001) The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose. Am. J. Physiol. 280, R929–R934.
70. Hansen C. N., Fisher L. C., Deibert R. J., Jakeman L. B., Zhang H., Noble-Haeusslein L., White S. and Basso D. M. (2013) Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice. J. Neurosci. 33, 13101–13111.
71. Hardingham G. E., Fukunaga Y. and Bading H. (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414.
72. Hawkins B. T. and Davis T. P. (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185.
73. Heidt T., Sager H. B., Courties G. et al. (2014) Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758.
74. Henry C. J., Huang Y., Wynne A. M. and Godbout J. P. (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav. Immun. 23, 309–317.
75. Holmin S., Mathiesen T., Shetye J. and Biberfeld P. (1995) Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir. (Wien) 132, 110–119.
76. Huang Y., Henry C. J., Dantzer R., Johnson R. W. and Godbout J. P. (2008) Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol. Aging 29, 1744–1753.
77. Huang E. Y., Tsai T. H., Kuo T. T., Tsai J. J., Tsui P. F., Chou Y. C., Ma H. I., Chiang Y. H. and Chen Y. H. (2014) Remote effects on the striatal dopamine system after fluid percussion injury. Behav. Brain Res. 267, 156–172.
78. Imeri L. and Opp M. R. (2009) How (and why) the immune system makes us sleep. Nat. Rev. Neurosci. 10, 199–210.
79. Iwata M., Ota K. T. and Duman R. S. (2013) The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav. Immun. 31, 105–114.
80. Janelidze S., Mattei D., Westrin A., Traskman-Bendz L. and Brundin L. (2011) Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav. Immun. 25, 335–339.
81. John G. R., Lee S. C. and Brosnan C. F. (2003) Cytokines: powerful regulators of glial cell activation. Neuroscientist 9, 10–22.
82. Johnson J. D., Campisi J., Sharkey C. M., Kennedy S. L., Nickerson M., Greenwood B. N. and Fleshner M. (2005) Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295–1307.
83. Johnson V. E., Stewart J. E., Begbie F. D., Trojanowski J. Q., Smith D. H. and Stewart W. (2013) Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28–42.
84. Jurgens H. A. and Johnson R. W. (2010) Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp. Neurol. 233, 40–48.
85. Kabiersch A., del Rey A., Honegger C. G. and Besedovsky H. O. (1988) Interleukin-1 induces changes in norepinephrine metabolism in the rat brain. Brain Behav. Immun. 2, 267–274.
86. Kaltschmidt B., Ndiaye D., Korte M. et al. (2006) NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol. Cell. Biol. 26, 2936–2946.
87. Kawasaki Y., Zhang L., Cheng J. K. and Ji R. R. (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 28, 5189–5194.
88. Keinan G., Friedland N., Kahneman D. and Roth D. (1999) The effect of stress on the suppression of erroneous competing responses. Anxiety Stress Coping 12, 455–476.
89. Kelley K. W., O'Connor J. C., Lawson M. A., Dantzer R., Rodriguez-Zas S. L. and McCusker R. H. (2013) Aging leads to prolonged duration of inflammation-induced depression-like behavior caused by Bacillus Calmette-Guerin. Brain Behav. Immun. 32, 63–69.
90. Kigerl K. A., Gensel J. C., Ankeny D. P., Alexander J. K., Donnelly D. J. and Popovich P. G. (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.
91. Kipnis J., Gadani S. and Derecki N. C. (2012) Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12, 663–669.
92. Kotter M. R., Setzu A., Sim F. J., Van Rooijen N. and Franklin R. J. (2001) Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 35, 204–212.
93. Kovesdi E., Kamnaksh A., Wingo D., Ahmed F., Grunberg N. E., Long J. B., Kasper C. E. and Agoston D. V. (2012) Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front. Neurol. 3, 111.
94. Kumar A. and Loane D. J. (2012) Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav. Immun. 26, 1191–1201.
95. Kumar A., Stoica B. A., Sabirzhanov B., Burns M. P., Faden A. I. and Loane D. J. (2013) Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol. Aging 34, 1397–1411.
96. Kumar A., Alvarez-Croda D. M., Stoica B. A., Faden A. I. and Loane D. J. (2015) Microglial/macrophage polarization dynamics following traumatic brain injury. J. Neurotrauma 33, 1–19.
97. Lacroix S., Feinstein D. and Rivest S. (1998) The bacterial endotoxin lipopolysaccharide has the ability to target the brain in upregulating its membrane CD14 receptor within specific cellular populations. Brain Pathol. 8, 625–640.
98. Laflamme N., Lacroix S. and Rivest S. (1999) An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J. Neurosci. 19, 10923–10930.
99. Liesz A., Zhou W., Mracsko E. et al. (2011) Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 134, 704–720.
100. Lifshitz J. (2009) Fluid percussion injury model. in Animal Models of Acute Neurological Injuries (Chen J., Xu Z. C., Xu X.-M. and Zhang J. H., eds), pp. 369. Humana Press, Totowa, NJ.
101. Lifshitz J., Kelley B. J. and Povlishock J. T. (2007a) Perisomatic thalamic axotomy after diffuse traumatic brain injury is associated with atrophy rather than cell death. J. Neuropathol. Exp. Neurol. 66, 218–229.
102. Lifshitz J., Witgen B. and Grady M. (2007b) Acute cognitive impairment after lateral fluid percussion brain injury recovers by 1 month: evaluation by conditioned fear response. Behav. Brain Res. 177, 347.
103. Linker R. A., Maurer M., Gaupp S. et al. (2002) CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat. Med. 8, 620–624.
104. Loane D. J., Kumar A., Stoica B. A., Cabatbat R. and Faden A. I. (2014) Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J. Neuropathol. Exp. Neurol. 73, 14–29.
105. Lovas G., Szilagyi N., Majtenyi K., Palkovits M. and Komoly S. (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123(), 308–317.
106. Lucin K. M. and Wyss-Coray T. (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64, 110–122.
107. Maas A. I., Stocchetti N. and Bullock R. (2008) Moderate and severe traumatic brain injury in adults. Lancet Neurol. 7, 728–741.
108. Mackenzie C. S., Smith M. C., Hasher L., Leach L. and Behl P. (2007) Cognitive functioning under stress: evidence from informal caregivers of palliative patients. J. Palliat. Med. 10, 749–758.
109. Maher F. O., Nolan Y. and Lynch M. A. (2005) Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat. Neurobiol. Aging 26, 717–728.
110. McAfoose J. and Baune B. T. (2009) Evidence for a cytokine model of cognitive function. Neurosci. Biobehav. Rev. 33, 355–366.
111. McCrea M., Guskiewicz K. M., Marshall S. W., Barr W., Randolph C., Cantu R. C., Onate J. A., Yang J. and Kelly J. P. (2003) Acute effects and recovery time following concussion in collegiate football players: the NCAA concussion study. JAMA 290, 2556.
112. McEwen B. S. (2013) The brain on stress: toward an integrative approach to brain, body and behavior. Perspect. Psychol. Sci. 8, 673–675.
113. Meffert M. K., Chang J. M., Wiltgen B. J., Fanselow M. S. and Baltimore D. (2003) NF-kappa B functions in synaptic signaling and behavior. Nat. Neurosci. 6, 1072–1078.
114. Michael B. D., Griffiths M. J., Granerod J. et al. (2015) The interleukin-1 balance is associated with clinical severity, blood-brain barrier permeability, neuroimaging changes and outcome in encephalitis. J. Infect. Dis. in press.
115. Monahan A. J., Warren M. and Carvey P. M. (2008) Neuroinflammation and peripheral immune infiltration in Parkinson's disease: an autoimmune hypothesis. Cell Transplant. 17, 363–372.
116. Morales D., Marklund N., Lebold D. et al. (2005) Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience 136, 971.
117. Morganti J. M., Jopson T. D., Liu S., Riparip L. K., Guandique C. K., Gupta N., Ferguson A. R. and Rosi S. (2015) CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J. Neurosci. 35, 748–760.
118. Mouzon B. C., Bachmeier C., Ferro A. et al. (2014) Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model. Ann. Neurol. 75, 241–254.
119. Mrak R. E., Sheng J. G. and Griffin W. S. (1995) Glial cytokines in Alzheimer's disease: review and pathogenic implications. Hum. Pathol. 26, 816–823.
120. Muccigrosso M. M., Ford J., Benner B. et al. (2016) Cognitive deficits develop 1 month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge. Brain Behav. Immun. in press.
121. Nesic O., Xu G. Y., McAdoo D., High K. W., Hulsebosch C. and Perez-Pol R. (2001) IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J. Neurotrauma 18, 947–956.
122. Netea M. G. (2013) Training innate immunity: the changing concept of immunological memory in innate host defence. Eur. J. Clin. Invest. 43, 881–884.
123. Newell E., Shellington D. K., Simon D. W. et al. (2015) Cerebrospinal fluid markers of macrophage and lymphocyte activation after traumatic brain injury in children. Pediatr. Crit. Care Med. 16, 549–557.
124. Nimmerjahn A., Kirchhoff F. and Helmchen F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318.
125. Norden D. M. and Godbout J. P. (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 39, 19–34.
126. Norden D. M., Fenn A. M., Dugan A. and Godbout J. P. (2014) TGFbeta produced by IL-10 redirected astrocytes attenuates microglial activation. Glia 62, 881–895.
127. Norden D. M., Trojanowski P. J., Villanueva E., Navarro E. and Godbout J. P. (2016) Sequential activation of microglia and astrocyte cytokine expression precedes increased iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia 64, 300–316.
128. Osier N., Carlson S. W., DeSana A. J. and Dixon C. E. (2014) Chronic histopathological and behavioral outcomes of experimental traumatic brain injury in adult male animals. J. Neurotrauma 32, 1861–1882.
129. Ota A., Ikeda T., Xia X. Y., Xia Y. X. and Ikenoue T. (2000) Hypoxic-ischemic tolerance induced by hyperthermic pretreatment in newborn rats. J. Soc. Gynecol. Investig. 7, 102–105.
130. Oz M., Lorke D. E., Hasan M. and Petroianu G. A. (2011) Cellular and molecular actions of methylene blue in the nervous system. Med. Res. Rev. 31, 93–117.
131. Palin K., Moreau M. L., Sauvant J., Orcel H., Nadjar A., Duvoid-Guillou A., Dudit J., Rabie A. and Moos F. (2009) Interleukin-6 activates arginine vasopressin neurons in the supraoptic nucleus during immune challenge in rats. Am. J. Physiol. Endocrinol. Metab. 296, E1289–E1299.
132. Pineau I., Sun L., Bastien D. and Lacroix S. (2010) Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Brain Behav. Immun. 24, 540–553.
133. Popovich P. G., Guan Z., Wei P., Huitinga I., van Rooijen N. and Stokes B. T. (1999) Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp. Neurol. 158, 351–365.
134. Powell N. D., Sloan E. K., Bailey M. T. et al. (2013) Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis. Proc. Natl Acad. Sci. USA 110, 16574–16579.
135. Probert L., Eugster H. P., Akassoglou K., Bauer J., Frei K., Lassmann H. and Fontana A. (2000) TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease. Brain 123(), 2005–2019.
136. Qian J., Zhu L., Li Q., Belevych N., Chen Q., Zhao F., Herness S. and Quan N. (2012) Interleukin-1R3 mediates interleukin-1-induced potassium current increase through fast activation of Akt kinase. Proc. Natl Acad. Sci. USA 109, 12189–12194.
137. Ramirez K., Niraula A. and Sheridan J. F. (2016) GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations. Brain Behav. Immun. 51, 154–168.
138. Ramlackhansingh A. F., Brooks D. J., Greenwood R. J. et al. (2011) Inflammation after trauma: microglial activation and traumatic brain injury. Ann. Neurol. 70, 374–383.
139. Reboldi A., Coisne C., Baumjohann D. et al. (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10, 514–523.
140. del Rey A., Balschun D., Wetzel W., Randolf A. and Besedovsky H. O. (2013) A cytokine network involving brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and TNFalpha operates during long-term potentiation and learning. Brain Behav. Immun. 33, 15–23.
141. Riediger T., Cordani C., Potes C. S. and Lutz T. A. (2010) Involvement of nitric oxide in lipopolysaccharide induced anorexia. Pharmacol. Biochem. Behav. 97, 112–120.
142. Rimaniol A. C., Haik S., Martin M., Le Grand R., Boussin F. D., Dereuddre-Bosquet N., Gras G. and Dormont D. (2000) Na+-dependent high-affinity glutamate transport in macrophages. J. Immunol. 164, 5430–5438.
143. Rosczyk H. A., Sparkman N. L. and Johnson R. W. (2008) Neuroinflammation and cognitive function in aged mice following minor surgery. Exp. Gerontol. 43, 840–846.
144. Russo M. V. and McGavern D. B. (2015) Immune surveillance of the CNS following infection and injury. Trends Immunol. 36, 637–650.
145. Salter M. W. and Beggs S. (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24.
146. Samoilova E. B., Horton J. L., Hilliard B., Liu T. S. and Chen Y. (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161, 6480–6486.
147. Sawicki C., McKim D., Wohleb E., Jarrett B., Reader B., Norden D., Godbout J. and Sheridan J. (2014) Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain. Neuroscience 302, 151–164.
148. Schafer D. P. and Stevens B. (2013) Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr. Opin. Neurobiol. 23, 1034–1040.
149. Schneider H., Pitossi F., Balschun D., Wagner A., del Rey A. and Besedovsky H. O. (1998) A neuromodulatory role of interleukin-1beta in the hippocampus. Proc. Natl Acad. Sci. USA 95, 7778–7783.
150. Schnieder T. P., Trencevska I., Rosoklija G., Stankov A., Mann J. J., Smiley J. and Dwork A. J. (2014) Microglia of prefrontal white matter in suicide. J. Neuropathol. Exp. Neurol. 73, 880–890.
151. Schonberg D. L., Popovich P. G. and McTigue D. M. (2007) Oligodendrocyte generation is differentially influenced by toll-like receptor (TLR) 2 and TLR4-mediated intraspinal macrophage activation. J. Neuropathol. Exp. Neurol. 66, 1124–1135.
152. Schuitemaker A., van der Doef T. F., Boellaard R. et al. (2012) Microglial activation in healthy aging. Neurobiol. Aging 33, 1067–1072.
153. Semple B. D., Bye N., Rancan M., Ziebell J. M. and Morganti-Kossmann M. C. (2010) Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice. J. Cereb. Blood Flow Metab. 30, 769–782.
154. Serrats J., Schiltz J. C., Garcia-Bueno B., van Rooijen N., Reyes T. M. and Sawchenko P. E. (2010) Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106.
155. Shan R., Szmydynger-Chodobska J., Warren O. U., Mohammad F., Zink B. J. and Chodobski A. (2016) A new panel of blood biomarkers for the diagnosis of mild traumatic brain injury/concussion in adults. J. Neurotrauma 33, 49–57.
156. Shechter R., Miller O., Yovel G. et al. (2013) Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38, 555–569.
157. Shultz S. R., Bao F., Weaver L. C., Cain D. P. and Brown A. (2013) Treatment with an anti-CD11d integrin antibody reduces neuroinflammation and improves outcome in a rat model of repeated concussion. J. Neuroinflammation 10, 26.
158. Sica A., Schioppa T., Mantovani A. and Allavena P. (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur. J. Cancer 42, 717–727.
159. Sierra A., Gottfried-Blackmore A. C., McEwen B. S. and Bulloch K. (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55, 412–424.
160. Sokolova A., Hill M. D., Rahimi F., Warden L. A., Halliday G. M. and Shepherd C. E. (2009) Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease. Brain Pathol. 19, 392–398.
161. Sokolowski J. D. and Mandell J. W. (2011) Phagocytic clearance in neurodegeneration. Am. J. Pathol. 178, 1416–1428.
162. Sroga J. M., Jones T. B., Kigerl K. A., McGaughy V. M. and Popovich P. G. (2003) Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J. Comp. Neurol. 462, 223–240.
163. Stein M., Keshav S., Harris N. and Gordon S. (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292.
164. Stichel C. C. and Luebbert H. (2007) Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol. Aging 28, 1507–1521.
165. Talley Watts L., Long J. A., Boggs R. C., Manga H., Huang S., Shen Q. and Duong T. Q. (2016) Delayed methylene blue improves lesion volume, multi-parametric quantitative magnetic resonance imaging measurements, and behavioral outcome after traumatic brain injury. J. Neurotrauma 33, 194–202.
166. Tang Y., Noda Y., Hasegawa T. and Nabeshima T. (1997) A concussive-like brain injury model in mice (I): impairment in learning and memory. J. Neurotrauma 14, 851–862.
167. Tansey M. G. and Goldberg M. S. (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37, 510–518.
168. Tarr A. J., Liu X., Reed N. S. and Quan N. (2014) Kinetic characteristics of euflammation: the induction of controlled inflammation without overt sickness behavior. Brain Behav. Immun. 42, 96–108.
169. Tasaki K., Ruetzler C. A., Ohtsuki T., Martin D., Nawashiro H. and Hallenbeck J. M. (1997) Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. Brain Res. 748, 267–270.
170. Torres-Platas S. G., Cruceanu C., Chen G. G., Turecki G. and Mechawar N. (2014) Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. 42, 50–59.
171. Turtzo L. C., Lescher J., Janes L., Dean D. D., Budde M. D. and Frank J. A. (2014) Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J. Neuroinflammation 11, 82.
172. Tynan R. J., Naicker S., Hinwood M., Nalivaiko E., Buller K. M., Pow D. V., Day T. A. and Walker F. R. (2010a) Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav. Immun. 24, 1058–1068.
173. Tynan R. J., Naicker S., Hinwood M., Nalivaiko E., Buller K. M., Pow D. V., Day T. A. and Walker F. R. (2010b) Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav. Immun. 24, 1058–1068.
174. Ullian E. M., Harris B. T., Wu A., Chan J. R. and Barres B. A. (2004) Schwann cells and astrocytes induce synapse formation by spinal motor neurons in culture. Mol. Cell Neurosci. 25, 241–251.
175. Velazquez A., Ortega M., Rojas S., Gonzalez-Olivan F. J. and Rodriguez-Baeza A. (2015) Widespread microglial activation in patients deceased from traumatic brain injury. Brain Inj. 29, 1126–1133.
176. Vitaliano P. P., Murphy M., Young H. M., Echeverria D. and Borson S. (2011) Does caring for a spouse with dementia promote cognitive decline? A hypothesis and proposed mechanisms. J. Am. Geriatr. Soc. 59, 900–908.
177. 4+ T cells protect injured CNS neurons via IL-4. J. Clin. Invest. 125, 2547.
178. Walter S., Letiembre M., Liu Y. et al. (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell. Physiol. Biochem. 20, 947–956.
179. Wang G., Zhang J., Hu X. et al. (2013) Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J. Cereb. Blood Flow Metab. 33, 1864–1874.
180. Weil Z. M., Gaier K. R. and Karelina K. (2014) Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury. Neurobiol. Dis. 70, 108–116.
181. Werner C. and Engelhard K. (2007) Pathophysiology of traumatic brain injury. Br. J. Anaesth. 99, 4–9.
182. Witcher K. G., Eiferman D. S. and Godbout J. P. (2015) Priming the inflammatory pump of the CNS after traumatic brain injury. Trends Neurosci. 38, 609–620.
183. Wohleb E. S., Hanke M. L., Corona A. W., Powell N. D., Stiner L. M., Bailey M. T., Nelson R. J., Godbout J. P. and Sheridan J. F. (2011) beta-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J. Neurosci. 31, 6277–6288.
184. Wohleb E. S., Fenn A. M., Pacenta A. M., Powell N. D., Sheridan J. F. and Godbout J. P. (2012) Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology 37, 1491–1505.
185. Wohleb E. S., Powell N. D., Godbout J. P. and Sheridan J. F. (2013) Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J. Neurosci. 33, 13820–13833.
186. Wohleb E. S., McKim D. B., Shea D. T., Powell N. D., Tarr A. J., Sheridan J. F. and Godbout J. P. (2014a) Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol. Psychiatry 75, 970–981.
187. Wohleb E. S., McKim D. B., Sheridan J. F. and Godbout J. P. (2014b) Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front. Neurosci. 8, 447.
188. Woodcock T. and Morganti-Kossmann M. C. (2013) The role of markers of inflammation in traumatic brain injury. Front. Neurol. 4, 18.
189. Wynne A. M., Henry C. J., Huang Y., Cleland A. and Godbout J. P. (2010) Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav. Immun. 24, 1190–1201.
190. Xie Z., Morgan T. E., Rozovsky I. and Finch C. E. (2003) Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp. Neurol. 182, 135–141.
191. Xiong Y., Mahmood A. and Chopp M. (2013) Animal models of traumatic brain injury. Nat. Rev. Neurosci. 14, 128–142.
192. Yang L., Blumbergs P. C., Jones N. R., Manavis J., Sarvestani G. T. and Ghabriel M. N. (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 (Phila Pa 1976) 29, 966–971.
193. Yang L., Jones N. R., Blumbergs P. C., Van Den Heuvel C., Moore E. J., Manavis J., Sarvestani G. T. and Ghabriel M. N. (2005) Severity-dependent expression of pro-inflammatory cytokines in traumatic spinal cord injury in the rat. J. Clin. Neurosci. 12, 276–284.
194. Ye S. M. and Johnson R. W. (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. NeuroImmunoModulation 9, 183–192.
195. Youm Y. H., Grant R. W., McCabe L. R. et al. (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532.
196. Zhang B., Bailey W. M., Braun K. J. and Gensel J. C. (2015a) Age decreases macrophage IL-10 expression: implications for functional recovery and tissue repair in spinal cord injury. Exp. Neurol. 273, 83–91.
197. Zhang B., Bailey W. M., Kopper T. J., Orr M. B., Feola D. J. and Gensel J. C. (2015b) Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury. J. Neuroinflammation 12, 218.
198. Zhou H., Lapointe B. M., Clark S. R., Zbytnuik L. and Kubes P. (2006) A requirement for microglial TLR4 in leukocyte recruitment into brain in response to lipopolysaccharide. J. Immunol. 177, 8103–8110.
199. Ziebell J. M., Taylor S. E., Cao T., Harrison J. L. and Lifshitz J. (2012) Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury. J. Neuroinflammation 9, 247.
200. Ziv Y., Ron N., Butovsky O., Landa G., Sudai E., Greenberg N., Cohen H., Kipnis J. and Schwartz M. (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275.
201. Zong S., Zeng G., Wei B., Xiong C. and Zhao Y. (2012) Beneficial effect of interleukin-1 receptor antagonist protein on spinal cord injury recovery in the rat. Inflammation 35, 520–526.