The brain cytokine orchestra in multiple sclerosis: from neuroinflammation to synaptopathology.
Chemokines
Cytokines
Experimental autoimmune encephalomyelitis
Multiple Sclerosis
Neuroinflammation
Neuromodulation
Synaptopathy
Journal
Molecular brain
ISSN: 1756-6606
Titre abrégé: Mol Brain
Pays: England
ID NLM: 101468876
Informations de publication
Date de publication:
23 Jan 2024
23 Jan 2024
Historique:
received:
21
11
2023
accepted:
18
01
2024
medline:
24
1
2024
pubmed:
24
1
2024
entrez:
23
1
2024
Statut:
epublish
Résumé
The central nervous system (CNS) is finely protected by the blood-brain barrier (BBB). Immune soluble factors such as cytokines (CKs) are normally produced in the CNS, contributing to physiological immunosurveillance and homeostatic synaptic scaling. CKs are peptide, pleiotropic molecules involved in a broad range of cellular functions, with a pivotal role in resolving the inflammation and promoting tissue healing. However, pro-inflammatory CKs can exert a detrimental effect in pathological conditions, spreading the damage. In the inflamed CNS, CKs recruit immune cells, stimulate the local production of other inflammatory mediators, and promote synaptic dysfunction. Our understanding of neuroinflammation in humans owes much to the study of multiple sclerosis (MS), the most common autoimmune and demyelinating disease, in which autoreactive T cells migrate from the periphery to the CNS after the encounter with a still unknown antigen. CNS-infiltrating T cells produce pro-inflammatory CKs that aggravate local demyelination and neurodegeneration. This review aims to recapitulate the state of the art about CKs role in the healthy and inflamed CNS, with focus on recent advances bridging the study of adaptive immune system and neurophysiology.
Identifiants
pubmed: 38263055
doi: 10.1186/s13041-024-01077-7
pii: 10.1186/s13041-024-01077-7
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
4Subventions
Organisme : National Recovery and Resilience Plan (NRRP), project MNESYS
ID : PE0000006
Informations de copyright
© 2024. The Author(s).
Références
Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20(23):6008. https://doi.org/10.3390/ijms20236008 .
doi: 10.3390/ijms20236008
pubmed: 31795299
pmcid: 6929211
Geginat J, Sallusto F, Lanzavecchia A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells. J Exp Med. 2001;194(12):1711–9. https://doi.org/10.1084/jem.194.12.1711 .
doi: 10.1084/jem.194.12.1711
pubmed: 11748273
pmcid: 2193568
Grunnet LG, Aikin R, Tonnesen MF, Paraskevas S, Blaabjerg L, Størling J, et al. Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells. Diabetes. 2009;58(8):1807–15. https://doi.org/10.2337/db08-0178 .
doi: 10.2337/db08-0178
pubmed: 19470609
pmcid: 2712790
Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: a general review. Int J Neurosci. 2017;127(7):624–33. https://doi.org/10.1080/00207454.2016.1212854 .
doi: 10.1080/00207454.2016.1212854
pubmed: 27412492
Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y. Neuroinflammation: microglia and T cells get ready to tango. Front Immunol. 2018;25(8):1905. https://doi.org/10.3389/fimmu.2017.01905 .
doi: 10.3389/fimmu.2017.01905
Clark DN, Begg LR, Filiano AJ. Unique aspects of IFN-γ/STAT1 signaling in neurons. Immunol Rev. 2022;311(1):187–204. https://doi.org/10.1111/imr.13092 .
doi: 10.1111/imr.13092
pubmed: 35656941
pmcid: 10120860
Guillery RW. Observations of synaptic structures: origins of the neuron doctrine and its current status. Philos Trans R Soc Lond B Biol Sci. 2005;360:1281–307.
pubmed: 16147523
doi: 10.1098/rstb.2003.1459
Yuste R. From the neuron doctrine to neural networks. Nat Rev Neurosci. 2015;16:487–97.
pubmed: 26152865
doi: 10.1038/nrn3962
Denk W, Briggman K, Helmstaedter M. Structural neurobiology: missing link to a mechanistic understanding of neural computation”. Nat Rev Neurosci. 2012;13:351–8.
pubmed: 22353782
doi: 10.1038/nrn3169
Hof PR, Kidd G, DeFelipe J, de Vellis J, Gama Sosa MA, Elder GA, et al. Cellular components of nervous tissue. In: Byrne JH, Heidelberger R, Waxham MN, editors., et al., From molecules to networks: an introduction to cellular and molecular neuroscience. 3rd ed. Cambridge: Academic Press; 2014. p. 3–21. https://doi.org/10.1016/B978-0-12-397179-1.00001-4 .
doi: 10.1016/B978-0-12-397179-1.00001-4
Bernaus A, Blanco S, Sevilla A. Glia crosstalk in neuroinflammatory diseases. Front Cell Neurosci. 2020;29(14):209.
doi: 10.3389/fncel.2020.00209
Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunol Rev. 2006;213:48–65. https://doi.org/10.1111/j.1600-065X.2006.00441.x .
doi: 10.1111/j.1600-065X.2006.00441.x
pubmed: 16972896
pmcid: 2633103
Marin I, Kipnis J. Learning and memory … and the immune system. Learn Mem. 2013;20:601–6.
pubmed: 24051097
pmcid: 3768198
doi: 10.1101/lm.028357.112
Shechter R, London A, Schwartz M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol. 2013;13:206–18.
pubmed: 23435332
doi: 10.1038/nri3391
Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991–9.
pubmed: 26077718
pmcid: 4493418
doi: 10.1084/jem.20142290
Tracey K. Reflex control of immunity. Nat Rev Immunol. 2009;9:418–28.
pubmed: 19461672
pmcid: 4535331
doi: 10.1038/nri2566
Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev. 2018;98:477–504.
pubmed: 29351513
doi: 10.1152/physrev.00039.2016
Sawada M, Suzumura A, Marunouchi T. Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci. 1995;13:253–64.
pubmed: 7572279
pmcid: 7135063
doi: 10.1016/0736-5748(94)00076-F
Heinisch S, Kirby LG. SDF-1alpha/CXCL12 enhances GABA and glutamate synaptic activity at serotonin neurons in the rat dorsal raphe nucleus. Neuropharmacology. 2010;58(2):501–14.
pubmed: 19755127
doi: 10.1016/j.neuropharm.2009.08.022
Louveau A, Harris TH, Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015;36:569–77.
pubmed: 26431936
pmcid: 4593064
doi: 10.1016/j.it.2015.08.006
McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev. 2009;33(3):355–66.
pubmed: 18996146
doi: 10.1016/j.neubiorev.2008.10.005
Nisticò R, Salter E, Nicolas C, Feligioni M, Mango D, Bortolotto ZA, Gressens P, Collingridge GL, Peineau S. Synaptoimmunology—roles in health and disease. Mol Brain. 2017;10(1):26.
pubmed: 28637489
pmcid: 5480158
doi: 10.1186/s13041-017-0308-9
Depino AM, Alonso M, Ferrari C, del Rey A, Anthony D, Besedovsky H, Medina JH, Pitossi F. Learning modulation by endogenous hippocampal IL-1: blockade of endogenous IL-1 facilitates memory formation. Hippocampus. 2004;14(4):526–35. https://doi.org/10.1002/hipo.10164 .
doi: 10.1002/hipo.10164
pubmed: 15224987
Stellwagen D, Malenka R. Synaptic scaling mediated by glial TNF-α. Nature. 2006;440:1054–9.
pubmed: 16547515
doi: 10.1038/nature04671
Santello M, Volterra A. TNFα in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638–47.
pubmed: 22749718
doi: 10.1016/j.tins.2012.06.001
Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70–82.
pubmed: 25445483
doi: 10.1016/j.neuropharm.2014.10.027
Falcicchia C, Tozzi F, Arancio O, Watterson DM, Origlia N. Involvement of p38 MAPK in synaptic function and dysfunction. Int J Mol Sci. 2020;21(16):5624.
pubmed: 32781522
pmcid: 7460549
doi: 10.3390/ijms21165624
Bodnar CN, Morganti JM, Bachstetter AD. Depression following a traumatic brain injury: uncovering cytokine dysregulation as a pathogenic mechanism. Neural Regen Res. 2018;13(10):1693–704.
pubmed: 30136679
pmcid: 6128046
doi: 10.4103/1673-5374.238604
Wang S, Cheng Q, Malik S, Yang J. Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther. 2000;292(2):497–504.
pubmed: 10640285
Pribiag H, Stellwagen D. TNF-α downregulates inhibitory neurotransmission through protein phosphatase 1-dependent trafficking of GABA(A) receptors. J Neurosci. 2013;33(40):15879–93.
pubmed: 24089494
pmcid: 6618471
doi: 10.1523/JNEUROSCI.0530-13.2013
Giacco V, Panattoni G, Medelin M, Bonechi E, Aldinucci A, Ballerini C, et al. Cytokine inflammatory threat, but not LPS one, shortens GABAergic synaptic currents in the mouse spinal cord organotypic cultures. J Neuroinflammation. 2019;16(1):127. https://doi.org/10.1186/s12974-019-1519-z .
doi: 10.1186/s12974-019-1519-z
pubmed: 31238967
pmcid: 6593520
Ren S, Breuillaud L, Yao W, Yin T, Norris KA, Zehntner SP, D’Adamio L. TNF-α-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem2R47H rats. J Biol Chem. 2021;296:100089.
pubmed: 33434745
doi: 10.1074/jbc.RA120.016395
Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005;25(12):3219–28.
pubmed: 15788779
pmcid: 6725093
doi: 10.1523/JNEUROSCI.4486-04.2005
Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W. The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006;1762(11–12):1068–82.
pubmed: 16806844
doi: 10.1016/j.bbadis.2006.05.002
Schäfers M, Sorkin L. Effect of cytokines on neuronal excitability. Neurosci Lett. 2008;437(3):188–93.
pubmed: 18420346
doi: 10.1016/j.neulet.2008.03.052
Sitcheran R, Gupta P, Fisher PB, Baldwin AS. Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. EMBO J. 2005;24(3):510–20.
pubmed: 15660126
pmcid: 548660
doi: 10.1038/sj.emboj.7600555
Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC. Cytokine effects on glutamate uptake by human astrocytes. NeuroImmunoModulation. 2000;7(3):153–9.
pubmed: 10754403
doi: 10.1159/000026433
Henstridge CM, Tzioras M, Paolicelli RC. Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration. Front Cell Neurosci. 2019;26(13):63.
doi: 10.3389/fncel.2019.00063
Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, Jin S, Takada N, Komatsu Y, Suzumura A. Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J. 2008;22(6):1797–806.
pubmed: 18198214
doi: 10.1096/fj.07-099499
Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017;17(1):49–59.
pubmed: 27916979
doi: 10.1038/nri.2016.123
Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1): a020412. https://doi.org/10.1101/cshperspect.a020412 .
doi: 10.1101/cshperspect.a020412
pubmed: 25561720
pmcid: 4292164
Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57(2):173–85. https://doi.org/10.1124/pr.57.2.4 .
doi: 10.1124/pr.57.2.4
pubmed: 15914466
Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26(9):485–95. https://doi.org/10.1016/j.it.2005.07.004 .
doi: 10.1016/j.it.2005.07.004
pubmed: 16039904
Alvarez JI, Teale JM. Multiple expression of matrix metalloproteinases in murine neurocysticercosis: Implications for leukocyte migration through multiple central nervous system barriers. Brain Res. 2008;1214:145–58.
pubmed: 18466882
pmcid: 2517245
doi: 10.1016/j.brainres.2008.03.036
Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013;19(12):1584–96. https://doi.org/10.1038/nm.3407 .
doi: 10.1038/nm.3407
pubmed: 24309662
pmcid: 4080800
Wilson EH, Weninger W, Hunter CA. Trafficking of immune cells in the central nervous system. J Clin Invest. 2010;120(5):1368–79. https://doi.org/10.1172/JCI41911 .
doi: 10.1172/JCI41911
pubmed: 20440079
pmcid: 2860945
Kivisäkk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci USA. 2003;100(14):8389–94. https://doi.org/10.1073/pnas.1433000100 .
doi: 10.1073/pnas.1433000100
pubmed: 12829791
pmcid: 166239
Haegele KF, Stueckle CA, Malin JP, Sindern E. Increase of CD8+ T-effector memory cells in peripheral blood of patients with relapsing-remitting multiple sclerosis compared to healthy controls. J Neuroimmunol. 2007;183(1–2):168–74. https://doi.org/10.1016/j.jneuroim.2006.09.008 .
doi: 10.1016/j.jneuroim.2006.09.008
pubmed: 17084910
Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12(9):623–35. https://doi.org/10.1038/nri3265 .
doi: 10.1038/nri3265
pubmed: 22903150
Croese T, Castellani G, Schwartz M. Immune cell compartmentalization for brain surveillance and protection. Nat Immunol. 2021;22(9):1083–92. https://doi.org/10.1038/s41590-021-00994-2 .
doi: 10.1038/s41590-021-00994-2
pubmed: 34429552
Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, et al. 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. 2009;10(5):514–23. https://doi.org/10.1038/ni.1716 .
doi: 10.1038/ni.1716
pubmed: 19305396
Smolders J, Remmerswaal EB, Schuurman KG, Melief J, van Eden CG, van Lier RA, et al. Characteristics of differentiated CD8(+) and CD4 (+) T cells present in the human brain. Acta Neuropathol. 2013;126(4):525–35. https://doi.org/10.1007/s00401-013-1155-0 .
doi: 10.1007/s00401-013-1155-0
pubmed: 23880787
Brynskikh A, Warren T, Zhu J, Kipnis J. Adaptive immunity affects learning behavior in mice. Brain Behav Immun. 2008;22(6):861–9. https://doi.org/10.1016/j.bbi.2007.12.008 .
doi: 10.1016/j.bbi.2007.12.008
pubmed: 18249087
Filiano AJ, Gadani SP, Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci. 2017;18(6):375–84. https://doi.org/10.1038/nrn.2017.39 .
doi: 10.1038/nrn.2017.39
pubmed: 28446786
pmcid: 5823005
Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010;207(5):1067–80. https://doi.org/10.1084/jem.20091419 .
doi: 10.1084/jem.20091419
pubmed: 20439540
pmcid: 2867291
Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, et al. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019;4(40):eaay5199. https://doi.org/10.1126/sciimmunol.aay5199 .
doi: 10.1126/sciimmunol.aay5199
pubmed: 31604844
pmcid: 6894940
de Lima KA, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF, Smirnov I, et al. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020;21(11):1421–9. https://doi.org/10.1038/s41590-020-0776-4 .
doi: 10.1038/s41590-020-0776-4
pmcid: 8496952
Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA. 2004;101(21):8180–5. https://doi.org/10.1073/pnas.0402268101 .
doi: 10.1073/pnas.0402268101
pubmed: 15141078
pmcid: 419577
Kerfoot SM, Norman MU, Lapointe BM, Bonder CS, Zbytnuik L, Kubes P. Reevaluation of P-selectin and alpha 4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis. J Immunol. 2006;176(10):6225–34. https://doi.org/10.4049/jimmunol.176.10.6225 .
doi: 10.4049/jimmunol.176.10.6225
pubmed: 16670333
Wolburg K, Gerhardt H, Schulz M, Wolburg H, Engelhardt B. Ultrastructural localization of adhesion molecules in the healthy and inflamed choroid plexus of the mouse. Cell Tissue Res. 1999;296(2):259–69.
pubmed: 10382270
doi: 10.1007/s004410051287
Bove R, Chitnis T. Sexual disparities in the incidence and course of MS. Clin Immunol. 2013;149(2):201–10. https://doi.org/10.1016/j.clim.2013.03.005 .
doi: 10.1016/j.clim.2013.03.005
pubmed: 23608496
Ghasemi N, Razavi S, Nikzad E. Multiple sclerosis: pathogenesis, symptoms. Diagn Cell-Based Therapy Cell J. 2017;19(1):1–10. https://doi.org/10.22074/cellj.2016.4867 .
doi: 10.22074/cellj.2016.4867
Dempsey LA. Molecular mimicry in MS. Nat Immunol. 2022;23(3):343. https://doi.org/10.1038/s41590-022-01156-8 .
doi: 10.1038/s41590-022-01156-8
pubmed: 35236961
Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296–301. https://doi.org/10.1126/science.abj8222 .
doi: 10.1126/science.abj8222
pubmed: 35025605
Kaskow BJ, Baecher-Allan C. Effector T cells in multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(4): a029025. https://doi.org/10.1101/cshperspect.a029025 .
doi: 10.1101/cshperspect.a029025
pubmed: 29358315
pmcid: 5880159
Salou M, Nicol B, Garcia A, Laplaud DA. Involvement of CD8(+) T Cells in multiple sclerosis. Front Immunol. 2015;6:604. https://doi.org/10.3389/fimmu.2015.00604 .
doi: 10.3389/fimmu.2015.00604
pubmed: 26635816
pmcid: 4659893
Battistini L, Piccio L, Rossi B, Bach S, Galgani S, Gasperini C, et al. CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1. Blood. 2003;101(12):4775–82. https://doi.org/10.1182/blood-2002-10-3309 .
doi: 10.1182/blood-2002-10-3309
pubmed: 12595306
Lucchinetti CF, Popescu BFG, Bunyan RF, Moll NM, Roemer SF, Lassmann H, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011;365:2188–97. https://doi.org/10.1056/NEJMoa1100648 .
doi: 10.1056/NEJMoa1100648
pubmed: 22150037
pmcid: 3282172
Karpus WJ. Cytokines and chemokines in the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2020;204(2):316–26. https://doi.org/10.4049/jimmunol.1900914 .
doi: 10.4049/jimmunol.1900914
pubmed: 31907274
Robinson AP, Harp CT, Noronha A, Miller SD. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol. 2014;122:173–89. https://doi.org/10.1016/B978-0-444-52001-2.00008-X .
doi: 10.1016/B978-0-444-52001-2.00008-X
pubmed: 24507518
pmcid: 3981554
Ben-Nun A, Wekerle H, Cohen IR. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol. 1981;11:195–9.
pubmed: 6165588
doi: 10.1002/eji.1830110307
Marchetti L, Engelhardt B. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation. Vasc Biol. 2020;2(1):H1–18. https://doi.org/10.1530/VB-19-0033 .
doi: 10.1530/VB-19-0033
pubmed: 32923970
pmcid: 7439848
Brambilla R, Morton PD, Ashbaugh JJ, Karmally S, Lambertsen KL, Bethea JR. Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia. 2014;62(3):452–67. https://doi.org/10.1002/glia.22616 .
doi: 10.1002/glia.22616
pubmed: 24357067
Laschinger M, Vajkoczy P, Engelhardt B. Encephalitogenic T cells use LFA-1 for transendothelial migration but not during capture and initial adhesion strengthening in healthy spinal cord microvessels in vivo. Eur J Immunol. 2002;32:3598–606. https://doi.org/10.1002/1521-4141(200212)32:12%3c3598::AIDIMMU3598%3e3.0.CO;2-6 .
doi: 10.1002/1521-4141(200212)32:12<3598::AIDIMMU3598>3.0.CO;2-6
pubmed: 12516546
Carrithers MD, Visintin I, Kang SJ, Janeway CA Jr. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain. 2000;123:1092–101. https://doi.org/10.1093/brain/123.6.1092 .
doi: 10.1093/brain/123.6.1092
pubmed: 10825349
Song X, Gao H, Qian Y. Th17 differentiation and their pro-inflammation function. Adv Exp Med Biol. 2014;841:99–151. https://doi.org/10.1007/978-94-017-9487-9_5 .
doi: 10.1007/978-94-017-9487-9_5
pubmed: 25261206
Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G. Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS ONE. 2010;5(11): e15531. https://doi.org/10.1371/journal.pone.0015531 .
doi: 10.1371/journal.pone.0015531
pubmed: 21209700
pmcid: 3000428
Alt C, Laschinger M, Engelhardt B. Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the bloodbrain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol. 2002;32:2133–44. https://doi.org/10.1002/1521-4141(200208)32:8%3c2133::AID-IMMU2133%3e3.0.CO;2-W .
doi: 10.1002/1521-4141(200208)32:8<2133::AID-IMMU2133>3.0.CO;2-W
pubmed: 12209625
Krumbholz M, Theil D, Steinmeyer F, Cepok S, Hemmer B, Hofbauer M, et al. CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol. 2007;190:72–9. https://doi.org/10.1016/j.jneuroim.2007.07.024 .
doi: 10.1016/j.jneuroim.2007.07.024
pubmed: 17825430
Vajkoczy P, Laschinger M, Engelhardt B. Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels. J Clin Investig. 2001;108:557–65. https://doi.org/10.1172/JCI12440 .
doi: 10.1172/JCI12440
pubmed: 11518729
pmcid: 209399
Steffen BJ, Butcher EC, Engelhardt B. Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse. Am J Pathol. 1994;145(1):189–201.
pubmed: 7518194
pmcid: 1887301
Glatigny S, Duhen R, Oukka M, Bettelli E. Cutting edge: loss of α4 integrin expression differentially affects the homing of Th1 and Th17 cells. J Immunol. 2011;187(12):6176–9. https://doi.org/10.4049/jimmunol.1102515 .
doi: 10.4049/jimmunol.1102515
pubmed: 22084440
Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, et al. Mice with a disrupted IFNgamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996;156:5–7.
pubmed: 8598493
doi: 10.4049/jimmunol.156.1.5
Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol. 1996;157:3223–7.
pubmed: 8871615
doi: 10.4049/jimmunol.157.8.3223
Sosa RA, Murphey C, Robinson RR, Forsthuber TG. IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation. Proc Natl Acad Sci USA. 2015;112(36):E5038–47. https://doi.org/10.1073/pnas.1505955112 .
doi: 10.1073/pnas.1505955112
pubmed: 26305941
pmcid: 4568689
White MPJ, Webster G, Leonard F, La Flamme AC. Innate IFN-γ ameliorates experimental autoimmune encephalomyelitis and promotes myeloid expansion and PDL-1 expression. Sci Rep. 2018;8(1):259. https://doi.org/10.1038/s41598-017-18543-z .
doi: 10.1038/s41598-017-18543-z
pubmed: 29321652
pmcid: 5762891
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25. https://doi.org/10.1016/s1074-7613(00)00070-4 .
doi: 10.1016/s1074-7613(00)00070-4
pubmed: 11114383
Segal BM, Dwyer BK, Shevach EM. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med. 1998;187(4):537–46. https://doi.org/10.1084/jem.187.4.537 .
doi: 10.1084/jem.187.4.537
pubmed: 9463404
pmcid: 2212155
Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol. 2002;169(12):7104–10. https://doi.org/10.4049/jimmunol.169.12.7104 .
doi: 10.4049/jimmunol.169.12.7104
pubmed: 12471147
Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8. https://doi.org/10.1038/nature01355 .
doi: 10.1038/nature01355
pubmed: 12610626
Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198(12):1951–7. https://doi.org/10.1084/jem.20030896 .
doi: 10.1084/jem.20030896
pubmed: 14662908
pmcid: 2194162
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, et al. Generation of pathogenic T(H)17 cells in the absence of TGFβ signalling. Nature. 2010;467(7318):967–71. https://doi.org/10.1038/nature09447 .
doi: 10.1038/nature09447
pubmed: 20962846
pmcid: 3108066
McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10(3):314–24. https://doi.org/10.1038/ni.1698 .
doi: 10.1038/ni.1698
pubmed: 19182808
pmcid: 2945605
Andreadou M, Ingelfinger F, De Feo D, Cramer TLM, Tuzlak S, Friebel E, et al. IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice. Nat Neurosci. 2023;26(10):1701–12. https://doi.org/10.1038/s41593-023-01435-z .
doi: 10.1038/s41593-023-01435-z
pubmed: 37749256
pmcid: 10545539
McQualter JL, Darwiche R, Ewing C, Onuki M, Kay TW, Hamilton JA, et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J Exp Med. 2001;194(7):873–82. https://doi.org/10.1084/jem.194.7.873 .
doi: 10.1084/jem.194.7.873
pubmed: 11581310
pmcid: 2193476
Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity. 2015;43(3):502–14. https://doi.org/10.1016/j.immuni.2015.08.010 .
doi: 10.1016/j.immuni.2015.08.010
pubmed: 26341401
Ponomarev ED, Shriver LP, Maresz K, Pedras-Vasconcelos J, Verthelyi D, Dittel BN. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J Immunol. 2007;178(1):39–48. https://doi.org/10.4049/jimmunol.178.1.39 .
doi: 10.4049/jimmunol.178.1.39
pubmed: 17182538
Matejuk A, Dwyer J, Ito A, Bruender Z, Vandenbark AA, Offner H. Effects of cytokine deficiency on chemokine expression in CNS of mice with EAE. J Neurosci Res. 2002;67(5):680–8. https://doi.org/10.1002/jnr.10156 .
doi: 10.1002/jnr.10156
pubmed: 11891780
Mandolesi G, Gentile A, Musella A, Centonze D. IL-1β dependent cerebellar synaptopathy in a mouse mode of multiple sclerosis. Cerebellum. 2015;14(1):19–22.
pubmed: 25326653
doi: 10.1007/s12311-014-0613-0
Rizzo FR, Musella A, De Vito F, Fresegna D, Bullitta S, Vanni V, et al. Tumor necrosis factor and interleukin-1β modulate synaptic plasticity during neuroinflammation. Neural Plast. 2018;14(2018):8430123.
Di Filippo M, Portaccio E, Mancini A, Calabresi P. Multiple sclerosis and cognition: synaptic failure and network dysfunction. Nat Rev Neurosci. 2018;19(10):599–609. https://doi.org/10.1038/s41583-018-0053-9 .
doi: 10.1038/s41583-018-0053-9
pubmed: 30158590
Vercellino M, Marasciulo S, Grifoni S, Vallino-Costassa E, Bosa C, Pasanisi MB, et al. Acute and chronic synaptic pathology in multiple sclerosis gray matter. Mult Scler. 2022;28(3):369–82.
pubmed: 34124960
doi: 10.1177/13524585211022174
Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009;29(11):3442–52. https://doi.org/10.1523/JNEUROSCI.5804-08.2009 .
doi: 10.1523/JNEUROSCI.5804-08.2009
pubmed: 19295150
pmcid: 6665268
van der Valk P, Amor S. Preactive lesions in multiple sclerosis. Curr Opin Neurol. 2009;22(3):207–13.
pubmed: 19417567
doi: 10.1097/WCO.0b013e32832b4c76
Jafari M, Schumacher AM, Snaidero N, Ullrich Gavilanes EM, Neziraj T, Kocsis-Jutka V, et al. Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation. Nat Neurosci. 2021;24(3):355–67.
pubmed: 33495636
doi: 10.1038/s41593-020-00780-7
Rossi S, Furlan R, De Chiara V, Motta C, Studer V, Mori F, et al. Interleukin-1β causes synaptic hyperexcitability in multiple sclerosis. Ann Neurol. 2012;71(1):76–83.
pubmed: 22275254
doi: 10.1002/ana.22512
Musumeci G, Grasselli G, Rossi S, De Chiara V, Musella A, Motta C, et al. Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-α and of IL-1β in experimental autoimmune encephalomyelitis. Neurobiol Dis. 2011;43(3):669–77.
pubmed: 21672630
doi: 10.1016/j.nbd.2011.05.018
Bellingacci L, Mancini A, Gaetani L, Tozzi A, Parnetti L, Di Filippo M. Synaptic dysfunction in multiple sclerosis: a red thread from inflammation to network disconnection. Int J Mol Sci. 2021;22(18):9753.
pubmed: 34575917
pmcid: 8469646
doi: 10.3390/ijms22189753
Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31(2):331–41.
pubmed: 19682929
doi: 10.1016/j.immuni.2009.08.001
Das Sarma J, Ciric B, Marek R, Sadhukhan S, Caruso ML, Shafagh J, et al. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation. 2009;28(6):14.
doi: 10.1186/1742-2094-6-14
Kostic M, Zivkovic N, Cvetanovic A, Stojanovic I, Colic M. IL-17 signalling in astrocytes promotes glutamate excitotoxicity: Indications for the link between inflammatory and neurodegenerative events in multiple sclerosis. Mult Scler Relat Disord. 2017;11:12–7.
pubmed: 28104249
doi: 10.1016/j.msard.2016.11.006
von Banchet GS, Boettger MK, König C, Iwakura Y, Bräuer R, Schaible HG. Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia. Mol Cell Neurosci. 2013;52:152–60.
doi: 10.1016/j.mcn.2012.11.006
Meng X, Zhang Y, Lao L, Saito R, Li A, Bäckman CM, et al. Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model. Pain. 2013;154(2):294–305.
pubmed: 23246025
doi: 10.1016/j.pain.2012.10.022
Chen C, Itakura E, Nelson GM, Sheng M, Laurent P, Fenk LA, et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature. 2017;542(7639):43–8.
pubmed: 28099418
pmcid: 5503128
doi: 10.1038/nature20818
Luo H, Liu HZ, Zhang WW, Matsuda M, Lv N, Chen G, et al. Interleukin-17 regulates neuron-glial communications, synaptic transmission, and neuropathic pain after chemotherapy. Cell Rep. 2019;29(8):2384-2397.e5.
pubmed: 31747607
doi: 10.1016/j.celrep.2019.10.085
Di Filippo M, Mancini A, Bellingacci L, Gaetani L, Mazzocchetti P, Zelante T, et al. Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis. Cell Rep. 2021;37(10):110094.
pubmed: 34879272
doi: 10.1016/j.celrep.2021.110094
Dikmen HO, Hemmerich M, Lewen A, Hollnagel JO, Chausse B, Kann O. GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ. J Neuroinflammation. 2020;17(1):235.
pubmed: 32782006
pmcid: 7418331
doi: 10.1186/s12974-020-01903-4
Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta Neuropathol. 2015;129(5):625–37.
pubmed: 25716179
doi: 10.1007/s00401-015-1402-7
Pierson ER, Goverman JM. GM-CSF is not essential for experimental autoimmune encephalomyelitis but promotes brain-targeted disease. JCI Insight. 2017;2(7): e92362.
pubmed: 28405624
pmcid: 5374070
doi: 10.1172/jci.insight.92362
Medelin M, Giacco V, Aldinucci A, Castronovo G, Bonechi E, Sibilla A, et al. Bridging pro-inflammatory signals, synaptic transmission and protection in spinal explants in vitro. Mol Brain. 2018;11(1):3.
pubmed: 29334986
pmcid: 5769440
doi: 10.1186/s13041-018-0347-x
Lo Sasso B, Agnello L, Bivona G, Bellia C, Ciaccio M. Cerebrospinal fluid analysis in multiple sclerosis diagnosis: an update. Medicina. 2019;55(6):245. https://doi.org/10.3390/medicina55060245 .
doi: 10.3390/medicina55060245
pubmed: 31167509
pmcid: 6630948
Zrzavy T, Höftberger R, Wimmer I, Berger T, Rommer P, Macher S. Longitudinal CSF findings in autoimmune encephalitis-a monocentric cohort study. Front Immunol. 2021;22(12):646940. https://doi.org/10.3389/fimmu.2021.646940 .
doi: 10.3389/fimmu.2021.646940
Jarius S, König FB, Metz I, Ruprecht K, Paul F, Brück W, et al. Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. J Neuroinflammation. 2017;14(1):171. https://doi.org/10.1186/s12974-017-0929-z .
doi: 10.1186/s12974-017-0929-z
pubmed: 28851393
pmcid: 5576197
Saruhan-Direskeneli G, Yentür SP, Mutlu M, Shugaiv E, Yesilot N, Kürtüncü M, et al. Intrathecal oligoclonal IgG bands are infrequently found in neuro-Behçet’s disease. Clin Exp Rheumatol. 2013;31(3 Suppl 77):25–7.
pubmed: 23558092
Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisakk P, Ransohoff RM, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain. 2006;129(Pt 1):200–11.
pubmed: 16280350
doi: 10.1093/brain/awh680
Khademi M, Kockum I, Andersson ML, Iacobaeus E, Brundin L, Sellebjerg F, et al. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult Scler. 2011;17(3):335–43. https://doi.org/10.1177/1352458510389102 .
doi: 10.1177/1352458510389102
pubmed: 21135023
DiSano KD, Gilli F, Pachner AR. Intrathecally produced CXCL13: a predictive biomarker in multiple sclerosis. Mult Scler J Exp Transl Clin. 2020;6(4):2055217320981396. https://doi.org/10.1177/2055217320981396 .
doi: 10.1177/2055217320981396
pubmed: 33403120
pmcid: 7747124
Kothur K, Wienholt L, Brilot F, Dale RC. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: a systematic review. Cytokine. 2016;77:227–37.
pubmed: 26463515
doi: 10.1016/j.cyto.2015.10.001
Dhaiban S, Al-Ani M, Elemam NM, Maghazachi AA. Targeting chemokines and chemokine receptors in multiple sclerosis and experimental autoimmune encephalomyelitis. J Inflamm Res. 2020;29(13):619–33. https://doi.org/10.2147/JIR.S270872 .
doi: 10.2147/JIR.S270872
D’Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S, Mantovani A, et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol. 1998;161(10):5111–5.
pubmed: 9820476
doi: 10.4049/jimmunol.161.10.5111
Poppensieker K, Otte DM, Schürmann B, Limmer A, Dresing P, Drews E, et al. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc Natl Acad Sci USA. 2012;109(10):3897–902. https://doi.org/10.1073/pnas.1114153109 .
doi: 10.1073/pnas.1114153109
pubmed: 22355103
pmcid: 3309768
Khaibullin T, Ivanova V, Martynova E, Cherepnev G, Khabirov F, Granatov E, et al. Elevated levels of proinflammatory cytokines in cerebrospinal fluid of multiple sclerosis patients. Front Immunol. 2017;8:531. https://doi.org/10.3389/fimmu.2017.00531 .
doi: 10.3389/fimmu.2017.00531
pubmed: 28572801
pmcid: 5435759
Kuhlmann T, Ludwin S, Prat A, Antel J, Bruck W, Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133:13–24. https://doi.org/10.1007/s00401-016-1653-y .
doi: 10.1007/s00401-016-1653-y
pubmed: 27988845
Peferoen LA, Vogel DY, Ummenthum K, Breur M, Heijnen PD, Gerritsen WH, et al. Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis. J Neuropathol Exp Neurol. 2015;74:48–63. https://doi.org/10.1097/NEN.0000000000000149 .
doi: 10.1097/NEN.0000000000000149
pubmed: 25470347
Donninelli G, Studer V, Brambilla L, Zecca C, Peluso D, Laroni A, Michelis D, Mantegazza R, Confalonieri P, Volpe E. Immune soluble factors in the cerebrospinal fluid of progressive multiple sclerosis patients segregate into two groups. Front Immunol. 2021;10(12):633167. https://doi.org/10.3389/fimmu.2021.633167 .
doi: 10.3389/fimmu.2021.633167
Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol. 1998;84(2):238–49. https://doi.org/10.1016/s0165-5728(97)00208-7 .
doi: 10.1016/s0165-5728(97)00208-7
pubmed: 9628469
Mahad DJ, Howell SJ, Woodroofe MN. Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;72(4):498–502. https://doi.org/10.1136/jnnp.72.4.498 .
doi: 10.1136/jnnp.72.4.498
pubmed: 11909910
pmcid: 1737819
Izikson L, Klein RS, Charo IF, Weiner HL, Luster AD. Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med. 2000;192(7):1075–80. https://doi.org/10.1084/jem.192.7.1075 .
doi: 10.1084/jem.192.7.1075
pubmed: 11015448
pmcid: 2193310
Huang DR, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM. Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med. 2001;193(6):713–26. https://doi.org/10.1084/jem.193.6.713 .
doi: 10.1084/jem.193.6.713
pubmed: 11257138
pmcid: 2193420
Franciotta D, Martino G, Zardini E, Furlan R, Bergamaschi R, Andreoni L, et al. Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies. J Neuroimmunol. 2001;115(1–2):192–8. https://doi.org/10.1016/s0165-5728(01)00261-2 .
doi: 10.1016/s0165-5728(01)00261-2
pubmed: 11282170
Sørensen TL, Ransohoff RM, Strieter RM, Sellebjerg F. Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis. Eur J Neurol. 2004;11(7):445–9. https://doi.org/10.1111/j.1468-1331.2004.00796.x .
doi: 10.1111/j.1468-1331.2004.00796.x
pubmed: 15257681
de Morales JMGR, Puig L, Daudén E, Cañete JD, Pablos JL, Martín AO, et al. Critical role of interleukin (IL)-17 in inflammatory and immune disorders: an updated review of the evidence focusing in controversies. Autoimmun Rev. 2020;19(1):102429. https://doi.org/10.1016/j.autrev.2019.102429 .
doi: 10.1016/j.autrev.2019.102429
Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 2010;129:311–21. https://doi.org/10.1111/j.1365-2567.2009.03240.x .
doi: 10.1111/j.1365-2567.2009.03240.x
pubmed: 20409152
pmcid: 2826676
Milovanovic J, Arsenijevic A, Stojanovic B, Kanjevac T, Arsenijevic D, Radosavljevic G, et al. Interleukin-17 in chronic inflammatory neurological diseases. Front Immunol. 2020;3(11):947. https://doi.org/10.3389/fimmu.2020.00947 .
doi: 10.3389/fimmu.2020.00947
Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest. 2006;116(5):1218–22. https://doi.org/10.1172/JCI28508 .
doi: 10.1172/JCI28508
pubmed: 16670765
pmcid: 1451213
Lovett-Racke AE, Racke MK. Chapter 5-role of IL-12/IL-23 in the pathogenesis of multiple sclerosis. In: Minagar A, editor. Neuroinflammation. 2nd ed. Cambridge: Academic Press; 2018. p. 115–39. https://doi.org/10.1016/B978-0-12-811709-5.00005-3 .
doi: 10.1016/B978-0-12-811709-5.00005-3
Matusevicius D, Kivisäkk P, He B, Kostulas N, Ozenci V, Fredrikson S, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5(2):101–4. https://doi.org/10.1177/135245859900500206 .
doi: 10.1177/135245859900500206
pubmed: 10335518
Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8(5):500–8. https://doi.org/10.1038/nm0502-500 .
doi: 10.1038/nm0502-500
pubmed: 11984595
Brucklacher-Waldert V, Sturner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain. 2009;132:3329–41.
pubmed: 19933767
doi: 10.1093/brain/awp289
Núñez C, Dema B, Cénit MC, Polanco I, Maluenda C, Arroyo R, et al. IL23R: a susceptibility locus for celiac disease and multiple sclerosis? Genes Immun. 2008;9(4):289–93. https://doi.org/10.1038/gene.2008.16 .
doi: 10.1038/gene.2008.16
pubmed: 18368064
Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH, Ustekinumab MS Investigators. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796–804. https://doi.org/10.1016/S1474-4422(08)70173-X .
doi: 10.1016/S1474-4422(08)70173-X
pubmed: 18703004
Panitch HS, Hirsch RL, Schindler J, Johnson KP. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987;37(7):1097–102. https://doi.org/10.1212/wnl.37.7.1097 .
doi: 10.1212/wnl.37.7.1097
pubmed: 3110648
Furlan R, Brambilla E, Ruffini F, Poliani PL, Bergami A, Marconi PC, et al. Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes. J Immunol. 2001;167(3):1821–9. https://doi.org/10.4049/jimmunol.167.3.1821 .
doi: 10.4049/jimmunol.167.3.1821
pubmed: 11466408
Lees JR, Cross AH. A little stress is good: IFN-gamma, demyelination, and multiple sclerosis. J Clin Invest. 2007;117(2):297–9. https://doi.org/10.1172/JCI31254 .
doi: 10.1172/JCI31254
pubmed: 17273549
pmcid: 1783822
Lin W, Bailey SL, Ho H, Harding HP, Ron D, Miller SD, et al. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J Clin Invest. 2007;117(2):448–56. https://doi.org/10.1172/JCI29571 .
doi: 10.1172/JCI29571
pubmed: 17273557
pmcid: 1783809
Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, et al. Granulocyte-macrophage colony-stimulating factor (gm-csf) and T-cell responses: What we do and don’t know. Cell Res. 2006;16:126–33. https://doi.org/10.1038/sj.cr.7310017 .
doi: 10.1038/sj.cr.7310017
pubmed: 16474424
Rasouli J, Ciric B, Imitola J, Gonnella P, Hwang D, Mahajan K, et al. Expression of gm-csf in t cells is increased in multiple sclerosis and suppressed by ifn-beta therapy. J Immunol. 2015;194:5085–93. https://doi.org/10.4049/jimmunol.1403243 .
doi: 10.4049/jimmunol.1403243
pubmed: 25917097
Constantinescu CS, Asher A, Fryze W, Kozubski W, Wagner F, Aram J, et al. Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015;2(4): e117. https://doi.org/10.1212/NXI.0000000000000117 .
doi: 10.1212/NXI.0000000000000117
pubmed: 26185773
pmcid: 4442097
Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015;7(310):310ra166. https://doi.org/10.1126/scitranslmed.aab4176 .
doi: 10.1126/scitranslmed.aab4176
pubmed: 26491076
Ireland SJ, Monson NL, Davis LS. Seeking balance: potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10. Cytokine. 2015;73(2):236–44. https://doi.org/10.1016/j.cyto.2015.01.009 .
doi: 10.1016/j.cyto.2015.01.009
pubmed: 25794663
pmcid: 4437890
Frei K, Fredrikson S, Fontana A, Link H. Interleukin-6 is elevated in plasma in multiple sclerosis. J Neuroimmunol. 1991;31(2):147–53. https://doi.org/10.1016/0165-5728(91)90020-8 .
doi: 10.1016/0165-5728(91)90020-8
pubmed: 1991821
Stampanoni Bassi M, Iezzi E, Drulovic J, Pekmezovic T, Gilio L, Furlan R, et al. IL-6 in the cerebrospinal fluid signals disease activity in multiple sclerosis. Front Cell Neurosci. 2020;23(14):120. https://doi.org/10.3389/fncel.2020.00120 .
doi: 10.3389/fncel.2020.00120
Aharoni R. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun Rev. 2013;12(5):543–53.
pubmed: 23051633
doi: 10.1016/j.autrev.2012.09.005
Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA, Joosten LA. Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol. 2015;33:49–77.
pubmed: 25493334
doi: 10.1146/annurev-immunol-032414-112306
Schiffenbauer J, Streit WJ, Butfiloski E, LaBow M, Edwards C 3rd, Moldawer LL. The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor. Clin Immunol. 2000;95:117–23.
pubmed: 10779405
doi: 10.1006/clim.2000.4851
Levesque SA, Pare A, Mailhot B, Bellver-Landete V, Kebir H, Lecuyer MA, et al. Myeloid cell transmigration across the CNS vasculature triggers IL-1beta-driven neuroinflammation during autoimmune encephalomyelitis in mice. J Exp Med. 2016;213:929–49.
pubmed: 27139491
pmcid: 4886360
doi: 10.1084/jem.20151437
Seppi D, Puthenparampil M, Federle L, Ruggero S, Toffanin E, Rinaldi F, et al. Cerebrospinal fluid IL-1beta correlates with cortical pathology load in multiple sclerosis at clinical onset. J Neuroimmunol. 2014;270:56–60.
pubmed: 24657029
doi: 10.1016/j.jneuroim.2014.02.014
Rossi S, Studer V, Motta C, Germani G, Macchiarulo G, Buttari F, et al. Cerebrospinal fluid detection of interleukin-1beta in phase of remission predicts disease progression in multiple sclerosis. J Neuroinflammation. 2014;11:32.
pubmed: 24548694
pmcid: 3975953
doi: 10.1186/1742-2094-11-32
Lin CC, Edelson BT. New insights into the role of IL-1β in experimental autoimmune encephalomyelitis and multiple sclerosis. J Immunol. 2017;198(12):4553–60. https://doi.org/10.4049/jimmunol.1700263 .
doi: 10.4049/jimmunol.1700263
pubmed: 28583987
Gough P, Myles IA. Tumor necrosis factor receptors: pleiotropic signaling complexes and their differential effects. Front Immunol. 2020;25(11):585880. https://doi.org/10.3389/fimmu.2020.585880 .
doi: 10.3389/fimmu.2020.585880
Kemanetzoglou E, Andreadou E. CNS demyelination with TNF-α blockers. Curr Neurol Neurosci Rep. 2017;17:36.
pubmed: 28337644
pmcid: 5364240
doi: 10.1007/s11910-017-0742-1
Zahid M, Busmail A, Penumetcha SS, Ahluwalia S, Irfan R, Khan SA, et al. Tumor necrosis factor alpha blockade and multiple sclerosis: exploring new avenues. Cureus. 2021;13(10): e18847. https://doi.org/10.7759/cureus.18847 .
doi: 10.7759/cureus.18847
pubmed: 34804701
pmcid: 8597935
Yang S, Wang J, Brand DD, Zheng SG. Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front Immunol. 2018;19(9):784. https://doi.org/10.3389/fimmu.2018.00784 .
doi: 10.3389/fimmu.2018.00784
Fensterl V, Sen GC. Interferons and viral infections. BioFactors. 2009;35(1):14–20. https://doi.org/10.1002/biof.6 .
doi: 10.1002/biof.6
pubmed: 19319841
Teige I, Treschow A, Teige A, Mattsson R, Navikas V, Leanderson T, et al. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J Immunol. 2003;170(9):4776–84. https://doi.org/10.4049/jimmunol.170.9.4776 .
doi: 10.4049/jimmunol.170.9.4776
pubmed: 12707359
Galligan CL, Pennell LM, Murooka TT, Baig E, Majchrzak-Kita B, Rahbar R, et al. Interferon-beta is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis. Mult Scler. 2010;16(12):1458–73. https://doi.org/10.1177/1352458510381259 .
doi: 10.1177/1352458510381259
pubmed: 20935030
Pennell LM, Fish EN. Interferon-β regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis. Immunology. 2017;152(3):439–50. https://doi.org/10.1111/imm.12781 .
doi: 10.1111/imm.12781
pubmed: 28646573
pmcid: 5629448
Wang D, Ghosh D, Islam SM, Moorman CD, Thomason AE, Wilkinson DS, et al. IFN-β facilitates neuroantigen-dependent induction of CD25+ FOXP3+ regulatory T cells that suppress experimental autoimmune encephalomyelitis. J Immunol. 2016;197(8):2992–3007. https://doi.org/10.4049/jimmunol.1500411 .
doi: 10.4049/jimmunol.1500411
pubmed: 27619998
Palle P, Monaghan KL, Milne SM, Wan ECK. Cytokine signaling in multiple sclerosis and its therapeutic applications. Med Sci. 2017;5(4):23. https://doi.org/10.3390/medsci5040023 .
doi: 10.3390/medsci5040023
Filipi M, Jack S. Interferons in the treatment of multiple sclerosis: a clinical efficacy, safety, and tolerability update. Int J MS Care. 2020;22(4):165–72. https://doi.org/10.7224/1537-2073.2018-063 .
doi: 10.7224/1537-2073.2018-063
pubmed: 32863784
D’Angelo C, Reale M, Costantini E, Di Nicola M, Porfilio I, de Andrés C, et al. Profiling of canonical and non-traditional cytokine levels in interferon-β-treated relapsing-remitting-multiple sclerosis patients. Front Immunol. 2018;4(9):1240. https://doi.org/10.3389/fimmu.2018.01240 .
doi: 10.3389/fimmu.2018.01240
Zhang L, Yuan S, Cheng G, Guo B. Type I IFN promotes IL-10 production from T cells to suppress Th17 cells and Th17-associated autoimmune inflammation. PLoS ONE. 2011;6(12): e28432. https://doi.org/10.1371/journal.pone.0028432 .
doi: 10.1371/journal.pone.0028432
pubmed: 22163016
pmcid: 3232207
Kubo M, Motomura Y. Transcriptional regulation of the anti-inflammatory cytokine IL-10 in acquired immune cells. Front Immunol. 2012;30(3):275. https://doi.org/10.3389/fimmu.2012.00275 .
doi: 10.3389/fimmu.2012.00275
Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol. 1998;161(7):3299–306.
pubmed: 9759845
doi: 10.4049/jimmunol.161.7.3299
Ozenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisäkk P, Fredrikson S, et al. Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment. Scand J Immunol. 1999;49(5):554–61. https://doi.org/10.1046/j.1365-3083.1999.00546.x .
doi: 10.1046/j.1365-3083.1999.00546.x
pubmed: 10320650
Carrieri PB, Ladogana P, Di Spigna G, de Leva MF, Petracca M, Montella S, et al. Interleukin-10 and interleukin-12 modulation in patients with relapsing-remitting multiple sclerosis on therapy with interferon-beta 1a: differences in responders and non responders. Immunopharmacol Immunotoxicol. 2008;30(4):1–9. https://doi.org/10.1080/08923970802302753 .
doi: 10.1080/08923970802302753
pubmed: 18686100
Gilio L, Buttari F, Pavone L, Iezzi E, Galifi G, Dolcetti E, et al. Fatigue in multiple sclerosis is associated with reduced expression of interleukin-10 and worse prospective disease activity. Biomedicines. 2022;10(9):2058. https://doi.org/10.3390/biomedicines10092058 .
doi: 10.3390/biomedicines10092058
pubmed: 36140159
pmcid: 9495727
Streeter HB, Rigden R, Martin KF, Scolding NJ, Wraith DC. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. Neurol Neuroimmunol Neuroinflamm. 2015;2(3): e93. https://doi.org/10.1212/NXI.0000000000000093 .
doi: 10.1212/NXI.0000000000000093
pubmed: 25798453
pmcid: 4360798
Chataway J, Martin K, Barrell K, Sharrack B, Stolt P, Wraith DC, et al. Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis. Neurology. 2018;90(11):e955–62. https://doi.org/10.1212/WNL.0000000000005118 .
doi: 10.1212/WNL.0000000000005118
pubmed: 29467307
Paul WE, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nat Rev Immunol. 2010;10(4):225–35. https://doi.org/10.1038/nri2735 .
doi: 10.1038/nri2735
pubmed: 20336151
pmcid: 3496776
Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Köhler G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993;362(6417):245–8. https://doi.org/10.1038/362245a0 .
doi: 10.1038/362245a0
pubmed: 8384701
Falcone M, Rajan AJ, Bloom BR, Brosnan CF. A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice. J Immunol. 1998;160(10):4822–30.
pubmed: 9590229
doi: 10.4049/jimmunol.160.10.4822
Liblau R, Steinman L, Brocke S. Experimental autoimmune encephalomyelitis in IL-4-deficient mice. Int Immunol. 1997;9(5):799–803. https://doi.org/10.1093/intimm/9.5.799 .
doi: 10.1093/intimm/9.5.799
pubmed: 9184926
Urcelay E, Santiago JL, Mas A, Martínez A, de Las HV, Arroyo R, et al. Role of interleukin 4 in Spanish multiple sclerosis patients. J Neuroimmunol. 2005;168(1–2):164–7. https://doi.org/10.1016/j.jneuroim.2005.07.004 .
doi: 10.1016/j.jneuroim.2005.07.004
pubmed: 16169606
Tahani S, Dehghani L, Jahanbani-Ardakani H, Shaygannejad V, Fazli A, Hamidavi A, et al. Elevated serum level of IL-4 in neuromyelitis optica and multiple sclerosis patients. J Immunoassay Immunochem. 2019;40(5):555–63. https://doi.org/10.1080/15321819.2019.1655649 .
doi: 10.1080/15321819.2019.1655649
pubmed: 31422745
Chan AH, Schroder K. Inflammasome signaling and regulation of interleukin-1 family cytokines. J Exp Med. 2020;217(1): e20190314. https://doi.org/10.1084/jem.20190314 .
doi: 10.1084/jem.20190314
pubmed: 31611248
Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, et al. Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis. Med. 2021;2(3):296-312.e8. https://doi.org/10.1016/j.medj.2021.01.006 .
doi: 10.1016/j.medj.2021.01.006
pubmed: 33748804
Mueller SN, Mackay LK. Tissue-resident memory T cells: local specialists in immune defence. Nat Rev Immunol. 2016;16(2):79–89. https://doi.org/10.1038/nri.2015.3 .
doi: 10.1038/nri.2015.3
pubmed: 26688350
Smolders J, van Luijn MM, Hsiao CC, Hamann J. T-cell surveillance of the human brain in health and multiple sclerosis. Semin Immunopathol. 2022;44(6):855–67. https://doi.org/10.1007/s00281-022-00926-8 .
doi: 10.1007/s00281-022-00926-8
pubmed: 35364699
pmcid: 9708786