Inflammation of the central nervous system (CNS) (neuroinflammation) is now recognized to be a feature of all neurological disorders. In multiple sclerosis, there is prominent infiltration of various leukocyte subsets into the CNS. Even when there is no significant inflammatory infiltrates, such as in Parkinson or Alzheimer disease, there is intense activation of microglia with resultant elevation of many inflammatory mediators within the CNS. An extensive dataset describes neuroinflammation to have detrimental consequences, but results emerging largely over the past decade have indicated that aspects of the inflammatory response are beneficial for CNS outcomes. Benefits of neuroinflammation now include neuroprotection, the mobilization of neural precursors for repair, remyelination, and even axonal regeneration. The findings that neuroinflammation can be beneficial should not be surprising as a properly directed inflammatory response in other tissues is a natural healing process after an insult. In this article, we review the data that highlight the dual aspects of neuroinflammation in being a hindrance on the one hand but also a significant help for recovery of the CNS on the other. We consider how the inflammatory response may be beneficial or injurious, and we describe strategies to harness the beneficial aspects of neuroinflammation.
Arnett HA, Mason J., Marino M., Suzuki K., Matsushima GK, Ting JP2001. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci4(11):1116-22.
2.
Baron R., Nemirovsky A., Harpaz I., Cohen H., Owens T., Monsonego A.2008. IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease. FASEB J22(8):2843-52.
3.
Bieber AJ, Kerr S., Rodriguez M.2003. Efficient central nervous system remyelination requires T cells. Ann Neurol53(5): 680-4.
4.
Chen Q., Smith GM, Shine HD2008. Immune activation is required for NT-3-induced axonal plasticity in chronic spinal cord injury. Exp Neurol209(2):497-509.
5.
Danilov AI, Covacu R., Moe MC, Langmoen IA, Johansson CB, Olsson T., and others. 2006. Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis. Eur J Neurosci23(2):394-400.
6.
DaSilva AG, Yong VW2008. Expression and regulation of matrix metalloproteinase-12 in experimental autoimmune encephalomyelitis and by bone marrow derived macrophages in vitro. J Neuroimmunol199(1-2):24-34.
7.
David S., Bouchard C., Tsatas O., Giftochristos N.1990. Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron5(4):463-9.
8.
Ferguson B., Matyszak MK, Esiri MM, Perry VH1997. Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt3): 393-9.
9.
Foote AK, Blakemore WF2005. Inflammation stimulates remyelination in areas of chronic demyelination. Brain 128 (Pt3):528-39.
10.
Giuliani F., Goodyer CG, Antel JP, Yong VW2003. Vulnerability of human neurons to T cell-mediated cytotoxicity . J Immunol171(1):368-79.
11.
Glass CK, Saijo K., Winner B., Marchetto MC, Gage FH2010. Mechanisms underlying inflammation in neurodegeneration . Cell140:918-34.
12.
Graber JJ, Dhib-Jalbut S.2009. Protective autoimmunity in the nervous system. Pharmacol Ther121(2):147-59.
13.
Hammarberg H., Lidman O., Lundberg C., Eltayeb SY, Gielen AW, Muhallab S., and others. 2000. Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci20(14):5283-91.
14.
Hendrix S., Nitsch R.2007. The role of T helper cells in neuroprotection and regeneration . J Neuroimmunol184(1-2): 100-12.
15.
Herx LM, Rivest S., Yong VW2000. Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol165(4):2232-9.
16.
Hirsch EC, Hunot S.2009. Neuroinflammation in Parkinson’s disease: a target for neuroprotection?Lancet Neurol8(4): 382-97.
17.
Imitola J., Raddassi K., Park KI, Mueller FJ, Nieto M., Teng YD, and others. 2004. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A101(52):18117-22.
18.
Irvine KA, Blakemore WF2008. Remyelination protects axons from demyelination-associated axon degeneration. Brain 131(Pt6):1464-77.
19.
Jones TB, Ankeny DP, Guan Z., McGaughy V., Fisher LC, Basso DM, and others. 2004. Passive or active immunization with myelin basic protein impairs neurological function and exacerbates neuropathology after spinal cord injury in rats. J Neurosci24(15):3752-61.
20.
Kebir H., Kreymborg K., Ifergan I., Dodelet-Devillers A., Cayrol R., Bernard M., and others. 2007. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med13(10):1173-5.
21.
Kerschensteiner M., Meinl E., Hohlfeld R.2009. Neuro-immune crosstalk in CNS diseases. Neuroscience158(3):1122-32.
22.
Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG2009. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci29(43):13435-44.
23.
Kigerl KA, Lai W., Rivest S., Hart RP, Satoskar AR, Popovich PG2007. Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem102(1):37-50.
24.
Kotter MR, Zhao C., van Rooijen N., Franklin RJ2005. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis18(1):166-75.
25.
Lalancette-Hebert M., Gowing G., Simard A., Weng YC, Kriz J.2007. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci27(10): 2596-605.
26.
Larsen PH, Wells JE, Stallcup WB, Opdenakker G., Yong VW2003. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J Neurosci23(35):11127-35.
27.
Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW2004. Pro-regenerative properties of cytokine-activated astrocytes . J Neurochem89(5):1092-100.
28.
Loughlin AJ, Copelman CA, Hall A., Armer T., Young BC, Landon DN, and others. 1997. Myelination and remyelination of aggregate rat brain cell cultures enriched with macrophages. J Neurosci Res47(4):384-92.
29.
Martinez FO, Helming L., Gordon S.2009. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol27:451-83.
30.
Medana I., Li Z., Flugel A., Tschopp J., Wekerle H., Neumann H.2001. Fas ligand (CD95L) protects neurons against perforinmediated T lymphocyte cytotoxicity. J Immunol167(2): 674-81.
31.
Nahrendorf M., Swirski FK, Aikawa E., Stangenberg L., Wurdinger T., Figueiredo JL, and others. 2007. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions . J Exp Med204(12):3037-47.
32.
Neumann H., Kotter MR, Franklin RJ2009. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain132(Pt 2):288-95.
33.
Nimmerjahn A., Kirchhoff F., Helmchen F.2005. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science308(5726):1314-8.
34.
Patrikios P., Stadelmann C., Kutzelnigg A., Rauschka H., Schmidbauer M., Laursen H., and others. 2006. Remyelination is extensive in a subset of multiple sclerosis patients. Brain129(Pt 12):3165-72.
35.
Penkowa M., Moos T., Carrasco J., Hadberg H., Molinero A., Bluethmann H., and others. 1999. Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice. Glia25(4):343-57.
36.
Popovich PG, Longbrake EE2008. Can the immune system be harnessed to repair the CNS? Nat Rev Neurosci9(6):481-93.
37.
Prewitt CM, Niesman IR, Kane CJ, Houle JD1997. Activated macrophage/microglial cells can promote the regeneration of sensory axons into the injured spinal cord. Exp Neurol148(2):433-43.
38.
Rice T., Larsen J., Rivest S., Yong VW2007. Characterization of the early neuroinflammation after spinal cord injury in mice. J Neuropathol Exp Neurol66(3):184-95.
39.
Rolls A., Shechter R., London A., Ziv Y., Ronen A., Levy R., and others. 2007. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol9(9):1081-8.
40.
Schwartz M., Moalem G., Leibowitz-Amit R., Cohen IR1999. Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci22(7):295-9.
41.
Setzu A., Lathia JD, Zhao C., Wells K., Rao MS, Ffrench-Constant C., and others. 2006. Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia54(4):297-303.
42.
Shechter R., London A., Varol C., Raposo C., Cusimano M., Yovel G., and others. 2009. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med6(7):e1000113.
43.
Simard AR, Soulet D., Gowing G., Julien JP, Rivest S.2006. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron49(4):489-502.
44.
Skihar V., Silva C., Chojnacki A., Doring A., Stallcup WB, Weiss S., and others. 2009. Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate. Proc Natl Acad Sci U S A106(42): 17992-7.
45.
Stirling DP, Liu S., Kubes P., Yong VW2009. Depletion of Ly6G/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome. J Neurosci29(3):753-64.
46.
Takeuchi H.2010. Neurotoxicity by microglia: mechanisms and potential therapeutic strategy. Clin Exp Neuroimmunol1:12-21.
47.
Turrin NP, Rivest S.2006. Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity . J Neurosci26(1):143-51.
48.
Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP 2nd, and others. 2006. Microglia instruct sub-ventricular zone neurogenesis. Glia54(8):815-25.
49.
Weber MS, Prod’homme T., Youssef S., Dunn SE, Rundle CD, Lee L., and others. 2007. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med13(8):935-43.
50.
Wolf SA, Fisher J., Bechmann I., Steiner B., Kwidzinski E., Nitsch R.2002. Neuroprotection by T-cells depends on their subtype and activation state. J Neuroimmunol133(1-2):72-80.
51.
Xue M., Fan Y., Liu S., Zygun DA, Demchuk A., Yong VW2009. Contributions of multiple proteases to neurotoxicity in a mouse model of intracerebral haemorrhage. Brain132(Pt 1):26-36.
52.
Yin Y., Cui Q., Gilbert HY, Yang Y., Yang Z., Berlinicke C., and others. 2009. Oncomodulin links inflammation to optic nerve regeneration. Proc Natl Acad Sci U S A106(46):19587-92.
53.
Yin Y., Henzl MT, Lorber B., Nakazawa T., Thomas TT, Jiang F., and others. 2006. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci9(6):843-52.
54.
Yong V., Ransohoff RM2002. Inflammatory cytokines in CNS trauma. In: Feuerstein G, editor. Inflammation and stroke . Basel: Birkhauser Verlag. p 181-92.
55.
Yong VW2002. Differential mechanisms of action of interferon-beta and glatiramer aetate in MS. Neurology59(6):802-8.
56.
Yong VW2004. Prospects for neuroprotection in multiple sclerosis. Front Biosci9:864-72.
57.
Yong VW, Wells J., Giuliani F., Casha S., Power C., Metz LM2004. The promise of minocycline in neurology. Lancet Neurol3(12):744-51.
58.
Zhao BQ, Wang S., Kim HY, Storrie H., Rosen BR, Mooney DJ, and others. 2006. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med12(4):441-5.
59.
Ziv Y., Ron N., Butovsky O., Landa G., Sudai E., Greenberg N., and others. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adult-hood. Nat Neurosci9(2):268-75.
60.
Zivadinov R., Reder AT, Filippi M., Minagar A., Stuve O., Lassmann H., and others. 2008. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology71(2):136-44.
