Log in

Resolution of neuroinflammation: mechanisms and potential therapeutic option

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The central nervous system (CNS) is comprised by an elaborate neural network that is under constant surveillance by tissue-intrinsic factors for maintenance of its homeostasis. Invading pathogens or sterile injuries might compromise vitally the CNS integrity and function. A prompt anti-inflammatory response is therefore essential to contain and repair the local tissue damage. Although the origin of the insults might be different, the principles of tissue backlashes, however, share striking similarities. CNS-resident cells, such as microglia and astrocytes, together with peripheral immune cells orchestrate an array of events that aim to functional restoration. If the acute inflammatory event remains unresolved, it becomes toxic leading to progressive CNS degeneration. Therefore, the cellular, molecular, and biochemical processes that regulate inflammation need to be on a fine balance with the intrinsic CNS repair mechanisms that influence tissue healing. The purpose of this review is to highlight aspects that facilitate the resolution of CNS inflammation, promote tissue repair, and functional recovery after acute injury and infection that could potentially contribute as therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Creagh EM, O’Neill LAJ (2006) TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27:352–357. https://doi.org/10.1016/j.it.2006.06.003

    Article  CAS  PubMed  Google Scholar 

  2. Hoving JC, Wilson GJ, Brown GD (2014) Signalling C-type lectin receptors, microbial recognition and immunity. Cell Microbiol 16:185–194. https://doi.org/10.1111/cmi.12249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820. https://doi.org/10.1016/j.cell.2010.01.022

    Article  CAS  PubMed  Google Scholar 

  4. Serhan CN, Chiang N, Dalli J (2015) The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. Semin Immunol 27:200–215. https://doi.org/10.1016/J.SMIM.2015.03.004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Basil MC, Levy BD (2016) Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol 16:51–67. https://doi.org/10.1038/nri.2015.4

    Article  CAS  PubMed  Google Scholar 

  6. Streit WJ, Mrak RE, Griffin WST (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1:14. https://doi.org/10.1186/1742-2094-1-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15:300–312. https://doi.org/10.1038/nrn3722

    Article  CAS  PubMed  Google Scholar 

  8. Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37:608–620. https://doi.org/10.1016/j.it.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  9. Popovich PG, Longbrake EE (2008) Can the immune system be harnessed to repair the CNS? Nat Rev Neurosci 9:481–493. https://doi.org/10.1038/nrn2398

    Article  CAS  PubMed  Google Scholar 

  10. Moynagh PN (2005) TLR signalling and activation of IRFs: revisiting old friends from the NF-kappaB pathway. Trends Immunol 26:469–476. https://doi.org/10.1016/j.it.2005.06.009

    Article  CAS  PubMed  Google Scholar 

  11. van den Pol AN, Ding S, Robek MD (2014) Long-distance interferon signaling within the brain blocks virus spread. J Virol 88:3695–3704. https://doi.org/10.1128/JVI.03509-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guo H, Callaway JB, Ting JP-Y (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687. https://doi.org/10.1038/nm.3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hanamsagar R, Aldrich A, Kielian T (2014) Critical role for the AIM2 inflammasome during acute CNS bacterial infection. J Neurochem 129:704–711. https://doi.org/10.1111/jnc.12669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Terry RL, Getts DR, Deffrasnes C, van Vreden C, Campbell IL, King NJC (2012) Inflammatory monocytes and the pathogenesis of viral encephalitis. J Neuroinflammation 9:776–710. https://doi.org/10.1186/1742-2094-9-270

    Article  Google Scholar 

  15. Duarte LF, Farías MA, Álvarez DM, Bueno SM, Riedel CA, González PA (2019) Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci 13:46. https://doi.org/10.3389/fncel.2019.00046

    Article  PubMed  PubMed Central  Google Scholar 

  16. McCandless EE, Zhang B, Diamond MS, Klein RS (2008) CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis. Proc Natl Acad Sci USA 105:11270–11275. https://doi.org/10.1073/pnas.0800898105

    Article  PubMed  PubMed Central  Google Scholar 

  17. Potokar M, Jorgačevski J, Zorec R (2019) Astrocytes in Flavivirus infections. Int J Mol Sci 20. https://doi.org/10.3390/ijms20030691

    Article  CAS  PubMed Central  Google Scholar 

  18. Shrestha B, Pinto AK, Green S, Bosch I, Diamond MS (2012) CD8+ T cells use TRAIL to restrict West Nile virus pathogenesis by controlling infection in neurons. J Virol 86:8937–8948. https://doi.org/10.1128/JVI.00673-12

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Guidotti LG, Chisari FV (2003) Noncytolytic control of viral infections by the innate and adaptive immune response. https://doi.org/10.1146/annurev.immunol19165

  20. Kim JV, Kang SS, Dustin ML, McGavern DB (2009) Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457:191–195. https://doi.org/10.1038/nature07591

    Article  CAS  PubMed  Google Scholar 

  21. Herz J, Johnson KR, McGavern DB (2015) Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells. J Exp Med 212:1153–1169. https://doi.org/10.1084/jem.20142047

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sitati EM, Diamond MS (2006) CD4+ T-cell responses are required for clearance of West Nile virus from the central nervous system. J Virol 80:12060–12069. https://doi.org/10.1128/JVI.01650-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lanteri MC, O’Brien KM, Purtha WE et al (2009) Tregs control the development of symptomatic West Nile virus infection in humans and mice. J Clin Invest 119:3266–3277. https://doi.org/10.1172/JCI39387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wu GF, Dandekar AA, Pewe L et al (2000) CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination. J Immunol 165:2278–2286. https://doi.org/10.4049/jimmunol.165.4.2278

    Article  CAS  PubMed  Google Scholar 

  25. Phares TW, Stohlman SA, Hwang M, Min B, Hinton DR, Bergmann CC (2012) CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J Virol 86:2416–2427. https://doi.org/10.1128/JVI.06797-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cervantes-Barragán L, Firner S, Bechmann I et al (2012) Regulatory T cells selectively preserve immune privilege of self-antigens during viral central nervous system infection. J Immunol 188:3678–3685. https://doi.org/10.4049/jimmunol.1102422

    Article  CAS  PubMed  Google Scholar 

  27. Trandem K, Anghelina D, Zhao J, Perlman S (2010) Regulatory T cells inhibit T cell proliferation and decrease demyelination in mice chronically infected with a coronavirus. J Immunol 184:4391–4400. https://doi.org/10.4049/jimmunol.0903918

    Article  CAS  PubMed  Google Scholar 

  28. Carbajal KS, Miranda JL, Tsukamoto MR, Lane TE (2011) CXCR4 signaling regulates remyelination by endogenous oligodendrocyte progenitor cells in a viral model of demyelination. Glia 59:1813–1821. https://doi.org/10.1002/glia.21225

    Article  PubMed  PubMed Central  Google Scholar 

  29. Genis P, Jett M, Bernton EW, Boyle T, Gelbard HA, Dzenko K, Keane RW, Resnick L, Mizrachi Y, Volsky DJ (1992) Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease. J Exp Med 176:1703–1718. https://doi.org/10.1084/jem.176.6.1703

    Article  CAS  PubMed  Google Scholar 

  30. Aliberti J, Hieny S, Reis e Sousa C et al (2002) Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat Immunol 3:76–82. https://doi.org/10.1038/ni745

    Article  CAS  PubMed  Google Scholar 

  31. Shryock N, McBerry C, Salazar Gonzalez RM et al (2013) Lipoxin A4 and 15-Epi-Lipoxin A4 protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain. PLoS One 8:e61882. https://doi.org/10.1371/journal.pone.0061882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mai NT, Dobbs N, Phu NH et al (2018) A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife 7. https://doi.org/10.7554/eLife.33478

  33. Prinz M, Erny D, Hagemeyer N (2017) Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 18:385–392. https://doi.org/10.1038/ni.3703

    Article  CAS  PubMed  Google Scholar 

  34. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Brück W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553. https://doi.org/10.1038/nn2015

    Article  CAS  PubMed  Google Scholar 

  35. Tay TL, Mai D, Dautzenberg J et al (2017) A new fate map** system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci 20:793–803. https://doi.org/10.1038/nn.4547

    Article  CAS  PubMed  Google Scholar 

  36. Villacampa N, Almolda B, Vilella A, Campbell IL, González B, Castellano B (2015) Astrocyte-targeted production of IL-10 induces changes in microglial reactivity and reduces motor neuron death after facial nerve axotomy. Glia 63:1166–1184. https://doi.org/10.1002/glia.22807

    Article  PubMed  Google Scholar 

  37. Osier ND, Carlson SW, DeSana A, Dixon CE (2015) Chronic histopathological and behavioral outcomes of experimental traumatic brain injury in adult male animals. J Neurotrauma 32:1861–1882. https://doi.org/10.1089/neu.2014.3680

    Article  PubMed  PubMed Central  Google Scholar 

  38. Corps KN, Roth TL, McGavern DB (2015) Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol 72:355. https://doi.org/10.1001/jamaneurol.2014.3558

    Article  PubMed  PubMed Central  Google Scholar 

  39. ** R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789. https://doi.org/10.1189/jlb.1109766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kigerl KA, Lai W, Rivest S, Hart RP, Satoskar AR, Popovich PG (2007) Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem 102:37–50. https://doi.org/10.1111/j.1471-4159.2007.04524.x

    Article  CAS  PubMed  Google Scholar 

  41. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758. https://doi.org/10.1038/nn1472

    Article  CAS  PubMed  Google Scholar 

  42. Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern D (2014) Transcranial amelioration of inflammation and cell death after brain injury. Nature 505:223–228. https://doi.org/10.1038/nature12808

    Article  CAS  PubMed  Google Scholar 

  43. **ong Y, Mahmood A, Chopp M (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14:128–142. https://doi.org/10.1038/nrn3407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Simon DW, McGeachy MJ, Bayır H, Clark RS, Loane DJ, Kochanek PM (2017) The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 13:171–191. https://doi.org/10.1038/nrneurol.2017.13

    Article  PubMed  PubMed Central  Google Scholar 

  45. Sandhir R, Puri V, Klein RM, Berman NEJ (2004) Differential expression of cytokines and chemokines during secondary neuron death following brain injury in old and young mice. Neurosci Lett 369:28–32. https://doi.org/10.1016/J.NEULET.2004.07.032

    Article  CAS  PubMed  Google Scholar 

  46. Chu HX, Arumugam TV, Gelderblom M, Magnus T, Drummond GR, Sobey CG (2014) Role of CCR2 in inflammatory conditions of the central nervous system. J Cereb Blood Flow Metab 34:1425–1429. https://doi.org/10.1038/jcbfm.2014.120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fenn AM, Gensel JC, Huang Y, Popovich PG, Lifshitz J, Godbout JP (2014) Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol Psychiatry 76:575–584. https://doi.org/10.1016/j.biopsych.2013.10.014

    Article  CAS  PubMed  Google Scholar 

  48. d’Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA (2012) Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation 9:521–511. https://doi.org/10.1186/1742-2094-9-31

    Article  CAS  Google Scholar 

  49. Shinozaki Y, Shibata K, Ikenaka K et al (2017) Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y 1 receptor downregulation. Cell Rep 19:1151–1164. https://doi.org/10.1016/j.celrep.2017.04.047

    Article  CAS  PubMed  Google Scholar 

  50. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew MV (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. J Neurosci 33:12870–12886. https://doi.org/10.1523/JNEUROSCI.2121-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Blixt J, Svensson M, Gunnarson E, Wanecek M (2015) Aquaporins and blood–brain barrier permeability in early edema development after traumatic brain injury. Brain Res 1611:18–28. https://doi.org/10.1016/J.BRAINRES.2015.03.004

    Article  CAS  PubMed  Google Scholar 

  52. Soares HD, Hicks RR, Smith D, McIntosh TK (1995) Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci 15:8223–8233. https://doi.org/10.1523/JNEUROSCI.15-12-08223.1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hsieh CL, Kim CC, Ryba BE, Niemi EC, Bando JK, Locksley RM, Liu J, Nakamura MC, Seaman WE (2013) Traumatic brain injury induces macrophage subsets in the brain. Eur J Immunol 43:2010–2022. https://doi.org/10.1002/eji.201243084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Morganti JM, Jopson TD, Liu S, Riparip LK, Guandique CK, Gupta N, Ferguson AR, Rosi S (2015) CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J Neurosci 35:748–760. https://doi.org/10.1523/JNEUROSCI.2405-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cao T, Thomas TC, Ziebell JM, Pauly JR, Lifshitz J (2012) Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat. Neuroscience 225:65–75. https://doi.org/10.1016/j.neuroscience.2012.08.058

    Article  CAS  PubMed  Google Scholar 

  56. Loane DJ, Kumar A, Stoica BA et al (2014) Progressive neurodegeneration after experimental brain trauma. J Neuropathol Exp Neurol 73:14–29. https://doi.org/10.1097/NEN.0000000000000021

    Article  CAS  PubMed  Google Scholar 

  57. 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. https://doi.org/10.1038/jcbfm.2013.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Turtzo L, Lescher J, Janes L, Dean DD, Budde MD, Frank JA (2014) Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J Neuroinflammation 11:82. https://doi.org/10.1186/1742-2094-11-82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. ** X, Ishii H, Bai Z, Itokazu T, Yamashita T (2012) Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS One 7:e41892. https://doi.org/10.1371/journal.pone.0041892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dai S-S, Zhou Y-G, Li W, An JH, Li P, Yang N, Chen XY, **ong RP, Liu P, Zhao Y, Shen HY, Zhu PF, Chen JF (2010) Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci 30:5802–5810. https://doi.org/10.1523/JNEUROSCI.0268-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Myer DJ, Gurkoff GG, Lee SM et al (2006) Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 129:2761–2772. https://doi.org/10.1093/brain/awl165

    Article  CAS  PubMed  Google Scholar 

  62. Penkowa M, Giralt M, Lago N, Camats J, Carrasco J, Hernández J, Molinero A, Campbell IL, Hidalgo J (2003) Astrocyte-targeted expression of IL-6 protects the CNSagainst a focal brain injury. Exp Neurol 181:130–148. https://doi.org/10.1016/S0014-4886(02)00051-1

    Article  CAS  PubMed  Google Scholar 

  63. Bye N, Carron S, Han X, Agyapomaa D, Ng SY, Yan E, Rosenfeld JV, Morganti-Kossmann MC (2011) Neurogenesis and glial proliferation are stimulated following diffuse traumatic brain injury in adult rats. J Neurosci Res 89:986–1000. https://doi.org/10.1002/jnr.22635

    Article  CAS  PubMed  Google Scholar 

  64. Ngwenya LB, Danzer SC (2018) Impact of traumatic brain injury on neurogenesis. Front Neurosci 12:1014. https://doi.org/10.3389/fnins.2018.01014

    Article  PubMed  Google Scholar 

  65. Carlson SW, Madathil SK, Sama DM, Gao X, Chen J, Saatman KE (2014) Conditional overexpression of insulin-like growth factor-1 enhances hippocampal neurogenesis and restores immature neuron dendritic processes after traumatic brain injury. J Neuropathol Exp Neurol 73:734–746. https://doi.org/10.1097/NEN.0000000000000092

    Article  CAS  PubMed  Google Scholar 

  66. Madathil SK, Carlson SW, Brelsfoard JM, Ye P, D’Ercole AJ, Saatman KE (2013) Astrocyte-specific overexpression of insulin-like growth Factor-1 protects hippocampal neurons and reduces behavioral deficits following traumatic brain injury in mice. PLoS One 8:e67204. https://doi.org/10.1371/journal.pone.0067204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Piao C-S, Stoica BA, Wu J, Sabirzhanov B, Zhao Z, Cabatbat R, Loane DJ, Faden AI (2013) Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury. Neurobiol Dis 54:252–263. https://doi.org/10.1016/j.nbd.2012.12.017

    Article  PubMed  PubMed Central  Google Scholar 

  68. Harrison JL, Rowe RK, Ellis TW, Yee NS, O’Hara BF, Adelson PD, Lifshitz J (2015) Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain Behav Immun 47:131–140. https://doi.org/10.1016/J.BBI.2015.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Vanden BRW, Davidsson J, Lidin E et al (2019) Brain tissue saving effects by single-dose intralesional administration of neuroprotectin D1 on experimental focal penetrating brain injury in rats. J Clin Neurosci 64:227–233. https://doi.org/10.1016/J.JOCN.2019.03.032

    Article  Google Scholar 

  70. Luo C-L, Li Q-Q, Chen X-P, Zhang XM, Li LL, Li BX, Zhao ZQ, Tao LY (2013) Lipoxin A4 attenuates brain damage and downregulates the production of pro-inflammatory cytokines and phosphorylated mitogen-activated protein kinases in a mouse model of traumatic brain injury. Brain Res 1502:1–10. https://doi.org/10.1016/J.BRAINRES.2013.01.037

    Article  CAS  PubMed  Google Scholar 

  71. Lewis MD (2016) Concussions, traumatic brain injury, and the innovative use of omega-3s. J Am Coll Nutr 35:469–475. https://doi.org/10.1080/07315724.2016.1150796

    Article  CAS  PubMed  Google Scholar 

  72. Yang L, Jones NR, Blumbergs PC, van den Heuvel C, Moore EJ, Manavis J, Sarvestani GT, Ghabriel MN (2005) Severity-dependent expression of pro-inflammatory cytokines in traumatic spinal cord injury in the rat. J Clin Neurosci 12:276–284. https://doi.org/10.1016/J.JOCN.2004.06.011

    Article  CAS  PubMed  Google Scholar 

  73. Bastien D, Bellver Landete V, Lessard M, Vallières N, Champagne M, Takashima A, Tremblay MÈ, Doyon Y, Lacroix S (2015) IL-1α gene deletion protects oligodendrocytes after spinal cord injury through upregulation of the survival factor Tox3. J Neurosci 35:10715–10730. https://doi.org/10.1523/JNEUROSCI.0498-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hansen CN, Fisher LC, Deibert RJ, Jakeman LB, Zhang H, Noble-Haeusslein L, White S, Basso DM (2013) Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice. J Neurosci 33:13101–13111. https://doi.org/10.1523/JNEUROSCI.1576-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J, Kim KW, Klein E, Kalchenko V, Bendel P, Lira SA, Jung S, Schwartz M (2013) Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38:555–569. https://doi.org/10.1016/j.immuni.2013.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Raposo C, Graubardt N, Cohen M, Eitan C, London A, Berkutzki T, Schwartz M (2014) CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles. J Neurosci 34:10141–10155. https://doi.org/10.1523/JNEUROSCI.0076-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Walsh JT, Hendrix S, Boato F, Smirnov I, Zheng J, Lukens JR, Gadani S, Hechler D, Gölz G, Rosenberger K, Kammertöns T, Vogt J, Vogelaar C, Siffrin V, Radjavi A, Fernandez-Castaneda A, Gaultier A, Gold R, Kanneganti TD, Nitsch R, Zipp F, Kipnis J (2015) MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest 125:699–714. https://doi.org/10.1172/JCI76210

    Article  PubMed  PubMed Central  Google Scholar 

  78. Kroner A, Greenhalgh AD, Zarruk JG, Passos Dos Santos R, Gaestel M, David S (2014) TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83:1098–1116. https://doi.org/10.1016/j.neuron.2014.07.027

    Article  CAS  PubMed  Google Scholar 

  79. Paterniti I, Melani A, Cipriani S, Corti F, Mello T, Mazzon E, Esposito E, Bramanti P, Cuzzocrea S, Pedata F (2011) Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects. J Neuroinflammation 8:31. https://doi.org/10.1186/1742-2094-8-31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155. https://doi.org/10.1523/JNEUROSCI.3547-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Herrmann JE, Imura T, Song B et al (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243. https://doi.org/10.1523/JNEUROSCI.1709-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang H-F, Liu X-K, Li R, Zhang P, Chu Z, Wang CL, Liu HR, Qi J, Lv GY, Wang GY, Liu B, Li Y, Wang YY (2017) Effect of glial cells on remyelination after spinal cord injury. Neural Regen Res 12:1724–1732. https://doi.org/10.4103/1673-5374.217354

    Article  PubMed Central  PubMed  Google Scholar 

  83. Dias DO, Kim H, Holl D et al (2018) Reducing pericyte-derived scarring promotes recovery after spinal cord injury. Cell 173:153–165.e22. https://doi.org/10.1016/j.cell.2018.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cheng J, Korte N, Nortley R, Sethi H, Tang Y, Attwell D (2018) Targeting pericytes for therapeutic approaches to neurological disorders. Acta Neuropathol 136:507–523. https://doi.org/10.1007/s00401-018-1893-0

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Martini AC, Berta T, Forner S, Chen G, Bento AF, Ji RR, Rae GA (2016) Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection. J Neuroinflammation 13:75. https://doi.org/10.1186/s12974-016-0540-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lu T, Wu X, Wei N, Liu X, Zhou Y, Shang C, Duan Y, Dong Y (2018) Lipoxin A4 protects against spinal cord injury via regulating Akt/nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 signaling. Biomed Pharmacother 97:905–910. https://doi.org/10.1016/J.BIOPHA.2017.10.092

    Article  CAS  PubMed  Google Scholar 

  87. Francos-Quijorna I, Santos-Nogueira E, Gronert K, Sullivan AB, Kopp MA, Brommer B, David S, Schwab JM, López-Vales R (2017) Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. J Neurosci 37:11731–11743. https://doi.org/10.1523/JNEUROSCI.1395-17.2017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Maeda A, Fadeel B (2014) Mitochondria released by cells undergoing TNF-α-induced necroptosis act as danger signals. Cell Death Dis 5:e1312–e1312. https://doi.org/10.1038/cddis.2014.277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Abe T, Shimamura M, Jackman K, Kurinami H, Anrather J, Zhou P, Iadecola C (2010) Key role of CD36 in toll-like receptor 2 signaling in cerebral ischemia. Stroke 41:898–904. https://doi.org/10.1161/STROKEAHA.109.572552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938. https://doi.org/10.1038/sj.jcbfm.9600582

    Article  CAS  PubMed  Google Scholar 

  91. Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A (2012) Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 18:911–917. https://doi.org/10.1038/nm.2749

    Article  CAS  PubMed  Google Scholar 

  92. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198. https://doi.org/10.1016/j.neuron.2010.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Patel AR, Ritzel R, McCullough LD, Liu F (2013) Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol 5:73–90

    PubMed  PubMed Central  Google Scholar 

  94. Szalay G, Martinecz B, Lénárt N, Környei Z, Orsolits B, Judák L, Császár E, Fekete R, West BL, Katona G, Rózsa B, Dénes Á (2016) Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun 7:11499. https://doi.org/10.1038/ncomms11499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Panickar KS, Norenberg MD (2005) Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia 50:287–298. https://doi.org/10.1002/glia.20181

    Article  PubMed  Google Scholar 

  96. Rosell A, Cuadrado E, Ortega-Aznar A et al (2008) MMP-9–positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 39:1121–1126. https://doi.org/10.1161/STROKEAHA.107.500868

    Article  CAS  PubMed  Google Scholar 

  97. Garcia-Bonilla L, Moore JM, Racchumi G, Zhou P, Butler JM, Iadecola C, Anrather J (2014) Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol 193:2531–2537. https://doi.org/10.4049/JIMMUNOL.1400918

    Article  CAS  PubMed  Google Scholar 

  98. Enzmann G, Mysiorek C, Gorina R, Cheng YJ, Ghavampour S, Hannocks MJ, Prinz V, Dirnagl U, Endres M, Prinz M, Beschorner R, Harter PN, Mittelbronn M, Engelhardt B, Sorokin L (2013) The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol 125:395–412. https://doi.org/10.1007/s00401-012-1076-3

    Article  PubMed  Google Scholar 

  99. Gliem M, Mausberg AK, Lee J-I, Simiantonakis I, van Rooijen N, Hartung HP, Jander S (2012) Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann Neurol 71:743–752. https://doi.org/10.1002/ana.23529

    Article  CAS  PubMed  Google Scholar 

  100. Hum PD, Subramanian S, Parker SM et al (2007) T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab 27:1798–1805. https://doi.org/10.1038/sj.jcbfm.9600482

    Article  CAS  Google Scholar 

  101. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17–producing γδT cells in the delayed phase of ischemic brain injury. Nat Med 15:946–950. https://doi.org/10.1038/nm.1999

    Article  CAS  PubMed  Google Scholar 

  102. Liesz A, Zhou W, Na S-Y, Hämmerling GJ, Garbi N, Karcher S, Mracsko E, Backs J, Rivest S, Veltkamp R (2013) Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. J Neurosci 33:17350–17362. https://doi.org/10.1523/JNEUROSCI.4901-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, Bazan NG (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278:43807–43817. https://doi.org/10.1074/jbc.M305841200

    Article  CAS  PubMed  Google Scholar 

  104. Bazan NG, Eady TN, Khoutorova L, Atkins KD, Hong S, Lu Y, Zhang C, Jun B, Obenaus A, Fredman G, Zhu M, Winkler JW, Petasis NA, Serhan CN, Belayev L (2012) Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp Neurol 236:122–130. https://doi.org/10.1016/J.EXPNEUROL.2012.04.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wu Y, Ye X-H, Guo P-P, Xu SP, Wang J, Yuan SY, Yao SL, Shang Y (2010) Neuroprotective effect of Lipoxin A4 methyl ester in a rat model of permanent focal cerebral ischemia. J Mol Neurosci 42:226–234. https://doi.org/10.1007/s12031-010-9355-8

    Article  CAS  PubMed  Google Scholar 

  106. Hawkins KE, DeMars KM, Alexander JC, de Leon LG, Pacheco SC, Graves C, Yang C, McCrea A, Frankowski JC, Garrett TJ, Febo M, Candelario-Jalil E (2017) Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: protective mechanisms and long-term effects on neurological recovery. Brain Behav 7:e00688. https://doi.org/10.1002/brb3.688

    Article  PubMed  PubMed Central  Google Scholar 

  107. Tanaka K, Ishikawa Y, Yokoyama M et al (2008) Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke 39:2052–2058. https://doi.org/10.1161/STROKEAHA.107.509455

    Article  CAS  PubMed  Google Scholar 

  108. Poppitt SD, Howe CA, Lithander FE, Silvers KM, Lin RB, Croft J, Ratnasabapathy Y, Gibson RA, Anderson CS (2009) Effects of moderate-dose omega-3 fish oil on cardiovascular risk factors and mood after ischemic stroke: a randomized, controlled trial. Stroke 40:3485–3492. https://doi.org/10.1161/STROKEAHA.109.555136

    Article  CAS  PubMed  Google Scholar 

  109. Garbagnati F, Cairella G, De Martino A et al (2009) Is antioxidant and n–3 supplementation able to improve functional status in poststroke patients? Results from the Nutristroke Trial. Cerebrovasc Dis 27:375–383. https://doi.org/10.1159/000207441

    Article  CAS  PubMed  Google Scholar 

  110. Lawrence T, Gilroy DW (2006) Chronic inflammation: a failure of resolution? Int J Exp Pathol 88:85–94. https://doi.org/10.1111/j.1365-2613.2006.00507.x

    Article  CAS  Google Scholar 

  111. Prinz M, Priller J (2017) The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 20:136–144. https://doi.org/10.1038/nn.4475

    Article  CAS  PubMed  Google Scholar 

  112. Priller J, Prinz M (2019) Targeting microglia in brain disorders. Science 365(80):32–33. https://doi.org/10.1126/science.aau9100

    Article  CAS  PubMed  Google Scholar 

  113. Kierdorf K, Masuda T, Jordão MJC, Prinz M (2019) Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat Rev Neurosci 20:547–562. https://doi.org/10.1038/s41583-019-0201-x

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

MP is supported by the Sobek Foundation, the Ernst-Jung Foundation, the German Research Foundation (SFB 992, SFB/TRR167, SFB1160, Reinhart-Koselleck-Grant). This study was supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy (CIBSS – EXC-2189 – Project ID 390939984).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marco Prinz.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

This article is a contribution to the special issue on Resolution of Inflammation in Chronic Diseases - Guest Editor: Markus Neurath

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dokalis, N., Prinz, M. Resolution of neuroinflammation: mechanisms and potential therapeutic option. Semin Immunopathol 41, 699–709 (2019). https://doi.org/10.1007/s00281-019-00764-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-019-00764-1

Keywords

Navigation