NEUROINFLAMMATION MECHANISMS, CLINICAL IMPLICATIONS, AND THERAPEUTIC APPROACHES

neuroinflamationkapak

NEUROINFLAMMATION IN DEMYELINATING DISEASES: ALWAYS PRESENT

İpek Güngör Doğan1
Serkan Demir2

1Şehit Prof. Dr. İlhan Varank Sancaktepe Training and Research Hospital, Department of Neurology, İstanbul, Türkiye
2 University of Health Sciences, Hamidiye Faculty of Medicine, Şehit Prof. Dr. İlhan Varank Sancaktepe, Department of Neurology, İstanbul, Türkiye

Güngör Doğan İ, Demir S. Neuroinflammation in Demyelinating Diseases: Always Present. In: Şahin Ş editor. Neuroinflammation: Mechanisms, Clinical Implications, and Therapeutic Approaches. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.11-24.

ABSTRACT

Demyelinating diseases of the central nervous system (CNS) are chronic immune disorders primarily characterized by damage to the myelin sheath, with neuroinflammation playing a central role in their pathogenesis. The interplay of genetic predisposition, environmental factors, and complex immune system interactions triggers and sustains neuroinflammation. In the pathogenesis of these diseases, inflammatory activity driven by lymphocytes, persistent activation of resident glial cells such as microglia and astrocytes, and the expression of inflammatory cytokines, chemokines, and chemokine receptors exacerbate the condition. These lead not only to acute injury but also to chronic mechanisms that cause permanent damage.

In recent years, advanced imaging techniques and serum and cerebrospinal fluid (CSF) biomarker analyses have emerged as valuable tools for early diagnosis, disease activity monitoring, and therapeutic response evaluation. Furthermore, a deeper understanding of neuroinflammation’s cellular and molecular mechanisms holds promise and instills hope for developing personalized therapeutic approaches.

This study examines neuroinflammation’s central role in the pathogenesis of demyelinating diseases and its impact on clinical outcomes. Additionally, it reviews the current literature on innovative therapeutic strategies aimed at controlling inflammatory processes and improving neurological functions, offering insights that may guide future research and clinical applications.

Keywords: Multiple sclerosis; Demyelinating diseases; Ependymoglial cells; Lymphocytes; Chemokines; Cytokines

Referanslar

  1. Compston A, Coles A. Multiple sclerosis. Lancet (London, England). 2008;372(9648):1502-1517. [Crossref]  [PubMed]
  2. Bjornevik K, Münz C, Cohen JI, Ascherio A. Epstein-Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat Rev Neurol. 2023;19(3):160-171. [Crossref]  [PubMed]
  3. Garton T, Gadani SP, Gill AJ, Calabresi PA. Neurodegeneration and demyelination in multiple sclerosis. Neuron. 2024;112(19):3231-3251. [Crossref]  [PubMed]  [PMC]
  4. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61-76. [Crossref]  [PubMed]
  5. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis op tica spectrum disorders. Neurology. 2015;85(2):177-189. [Crossref]  [PubMed]  [PMC]
  6. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet (London, England). 2004;364(9451):2106-2112. [Crossref]  [PubMed]
  7. Takai Y, Misu T, Suzuki H, et al. Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders. Brain. 2021;144(8):2401-2415. [Crossref]  [PubMed]
  8. Carnero Contentti E, Correale J. Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies. J Neuroinflammation. 2021;18(1):208. [Crossref]  [PubMed]  [PMC]
  9. Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation. 2018;15(1):134. [Crossref]  [PubMed]  [PMC]
  10. Sechi E, Cacciaguerra L, Chen JJ, et al. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Review of Clinical and MRI Features, Diagnosis, and Management. Front Neurol. 2022;13:885218. [Crossref]  [PubMed]  [PMC]
  11. Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y. Neuroinflammation: Microglia and T Cells Get Ready to Tango. Front Immunol. 2017;8:1905. [Crossref]  [PubMed]  [PMC]
  12. Lassmann H. Multiple Sclerosis Pathology. Cold Spring Harb Perspect Med. 2018;8(3). [Crossref]  [PubMed]  [PMC]
  13. Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353(6301):777-783. [Crossref]  [PubMed]
  14. Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev. 2018;98(1):477-504. [Crossref]  [PubMed]  [PMC]
  15. 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 Off J Int Soc Dev Neurosci. 1995;13(3-4):253-264. [Crossref]  [PubMed]  [PMC]
  16. Amoriello R, Memo C, Ballerini L, Ballerini C. The brain cytokine orchestra in multiple sclerosis: from neuroinflammation to synaptopathology. Mol Brain. 2024;17(1):4. [Crossref]  [PubMed]  [PMC]
  17. Lin C-C, Edelson BT. New Insights into the Role of IL1 in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. J Immunol. 2017;198(12):4553-4560. [Crossref]  [PubMed]  [PMC]
  18. Rossi S, Studer V, Motta C, et al. Cerebrospinal fluid detection of interleukin-1 in phase of remission predicts disease progression in multiple sclerosis. J Neuroinflammation. 2014;11:32. [Crossref]  [PubMed]  [PMC]
  19. Seppi D, Puthenparampil M, Federle L, et al. Cerebrospinal fluid IL-1 correlates with cortical pathology load in multiple sclerosis at clinical onset. J Neuroimmunol. 2014;270(12):56-60. [Crossref]  [PubMed]
  20. Mizuno T, Zhang G, Takeuchi H, et al. Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J Off Publ Fed Am Soc Exp Biol. 2008;22(6):1797-1806. [Crossref]  [PubMed]
  21. 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):1097-1102. [Crossref]  [PubMed]
  22. 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):236-244. [Crossref]  [PubMed]  [PMC]
  23. Stampanoni Bassi M, Iezzi E, Drulovic J, et al. IL-6 in the Cerebrospinal Fluid Signals Disease Activity in Multiple Sclerosis. Front Cell Neurosci. 2020;14:120. [Crossref]  [PubMed]  [PMC]
  24. Wang Y, Zhang J, Chang H, et al. NMO-IgG Induce Interleukin-6 Release via Activation of the NF-B Signaling Pathway in Astrocytes. Neuroscience. 2022;496:96-104. [Crossref]  [PubMed]
  25. Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 2010;129(3):311-321.2567.2009.03240.x. [Crossref]  [PubMed]  [PMC]
  26. Tzartos JS, Friese MA, Craner MJ, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008;172(1):146-155. [Crossref]  [PubMed]  [PMC]
  27. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain. 2009;132(Pt 12):3329-3341. [Crossref]  [PubMed]
  28. Magliozzi R, Howell OW, Nicholas R, et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann Neurol. 2018;83(4):739-755. [Crossref]  [PubMed]
  29. Fresegna D, Bullitta S, Musella A, et al. Re-Examining the Role of TNF in MS Pathogenesis and Therapy. Cells. 2020;9(10). [Crossref]  [PubMed]  [PMC]
  30. Jiao L, Guo S. Anti-IL-6 therapies in central nervous system inflammatory demyelinating diseases. Front Immunol. 2022;13:966766. [Crossref]  [PubMed]  [PMC]
  31. Ruiz de Morales JMG, Puig L, Daudén E, 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. [Crossref]  [PubMed]
  32. Baggiolini M. Chemokines and leukocyte traffic. Nature. 1998;392(6676):565-568. [Crossref]  [PubMed]
  33. Ghafouri-Fard S, Honarmand K, Taheri M. A comprehensive review on the role of chemokines in the pathogenesis of multiple sclerosis. Metab Brain Dis. 2021;36(3):375-406. [Crossref]  [PubMed]
  34. Cui L-Y, Chu S-F, Chen N-H. The role of chemokines and chemokine receptors in multiple sclerosis. Int Immunopharmacol. 2020;83:106314. [Crossref]  [PubMed]  [PMC]
  35. Mahad DJ, Howell SJL, 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.
  36. Khademi M, Kockum I, Andersson ML, et al. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult Scler. 2011;17(3):335-343. [Crossref]  [PubMed]
  37. Khaibullin T, Ivanova V, Martynova E, et al. Elevated Levels of Proinflammatory Cytokines in Cerebrospinal Fluid of Multiple Sclerosis Patients. Front Immunol. 2017;8:531. [Crossref]  [PubMed]  [PMC]
  38. Stadelmann C, Timmler S, Barrantes-Freer A, Simons M. Myelin in the Central Nervous System: Structure, Function, and Pathology. Physiol Rev. 2019;99(3):1381-1431. [Crossref]  [PubMed]
  39. Coutinho Costa VG, Araújo SE-S, Alves-Leon SV, Gomes FCA. Central nervous system demyelinating diseases: glial cells at the hub of pathology. Front Immunol. 2023;14:1135540. [Crossref]  [PubMed]  [PMC]
  40. Lee H-G, Wheeler MA, Quintana FJ. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov. 2022;21(5):339-358. [Crossref]  [PubMed]  [PMC]
  41. Ponath G, Ramanan S, Mubarak M, et al. Myelin phago cytosis by astrocytes after myelin damage promotes lesion pathology. Brain. 2017;140(2):399-413. [Crossref]  [PubMed]  [PMC]
  42. Zhang X, Chen F, Sun M, et al. Microglia in the context of multiple sclerosis. Front Neurol. 2023;14:1157287. [Crossref]  [PubMed]  [PMC]
  43. Chu E, Mychasiuk R, Hibbs ML, Semple BD. Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation. J Neuroinflammation. 2021;18(1):276. [Crossref]  [PubMed]  [PMC]
  44. Rawji KS, Mishra MK, Yong VW. Regenerative Capacity of Macrophages for Remyelination. Front cell Dev Biol. 2016;4:47. [Crossref]  [PubMed]  [PMC]
  45. Enrich-Bengoa J, Manich G, Dégano IR, Perálvarez-Marín A. Deciphering the Genetic Crosstalk between Microglia and Oligodendrocyte Precursor Cells during Demyelination and Remyelination Using Transcriptomic Data. Int J Mol Sci. 2022;23(23). [Crossref]  [PubMed]  [PMC]
  46. Matejuk A, Ransohoff RM. Crosstalk Between Astrocytes and Microglia: An Overview. Front Immunol. 2020;11:1416. [Crossref]  [PubMed]  [PMC]
  47. Pukoli D, Vécsei L. Smouldering Lesion in MS: Microglia, Lymphocytes and Pathobiochemical Mechanisms. Int J Mol Sci. 2023;24(16). [Crossref]  [PubMed]  [PMC]
  48. Dal-Bianco A, Grabner G, Kronnerwetter C, et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 2017;133(1):25-42. [Crossref]  [PubMed]  [PMC]
  49. Scalfari A, Traboulsee A, Oh J, et al. Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann Neurol. 2024;96(5):826845. [Crossref]  [PubMed]
  50. Geladaris A, Torke S, Weber MS. Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression? CNS Drugs. 2022;36(10):10191030. [Crossref]  [PubMed]  [PMC]
  51. Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 2016;15(2):198-209. [Crossref]  [PubMed]
  52. Arneth B. Contributions of T cells in multiple sclerosis: what do we currently know? J Neurol. 2021;268(12):4587-4593. [Crossref]  [PubMed]
  53. Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1-13. [Crossref]  [PubMed]
  54. Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25(6):313-319. [Crossref]  [PubMed]
  55. Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med. 2000;192(3):393-404. [Crossref]  [PubMed]  [PMC]
  56. Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17(2):210-218.3639.2007.00064.x. [Crossref]  [PubMed]  [PMC]
  57. Mishra S, Srinivasan S, Ma C, Zhang N. CD8(+) Regulatory T Cell A Mystery to Be Revealed. Front Immunol. 2021;12:708874. [Crossref]  [PubMed]  [PMC]
  58. Fehérvari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest. 2004;114(9):1209-1217. [Crossref]  [PubMed]  [PMC]
  59. Liu R, Du S, Zhao L, et al. Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target. Front Immunol. 2022;13:996469. [Crossref]  [PubMed]  [PMC]
  60. van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers. Front Immunol. 2020;11:760. [Crossref]  [PubMed]  [PMC]
  61. Comi G, Bar-Or A, Lassmann H, et al. Role of B Cells in Multiple Sclerosis and Related Disorders. Ann Neurol. 2021;89(1):13-23. [Crossref]  [PubMed]  [PMC]
  62. Disanto G, Morahan JM, Barnett MH, Giovannoni G, Ramagopalan S V. The evidence for a role of B cells in multiple sclerosis. Neurology. 2012;78(11):823-832. [Crossref]  [PubMed]  [PMC]
  63. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodri guez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707-717. [Crossref]  [PubMed]
  64. Häusser-Kinzel S, Weber MS. The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders. Front Immunol. 2019;10:201. [Crossref]  [PubMed]  [PMC]
  65. Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(Pt 4):1089-1104. [Crossref]  [PubMed]
  66. Howell OW, Reeves CA, Nicholas R, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011;134(Pt 9):2755-2771. [Crossref]  [PubMed]
  67. Soltys J, Liu Y, Ritchie A, et al. Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica. J Clin Invest. 2019;129(5):2000-2013. [Crossref]  [PubMed]  [PMC]
  68. Yandamuri SS, Filipek B, Obaid AH, et al. MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity. JCI insight. 2023;8(11). [Crossref]  [PubMed]  [PMC]
  69. Moseley CE, Virupakshaiah A, Forsthuber TG, Steinman L, Waubant E, Zamvil SS. MOG CNS Autoimmunity and MOGAD. Neurol Neuroimmunol neuroinflammation. 2024;11(5):e200275. [Crossref]  [PubMed]  [PMC]
  70. Sechi E, Buciuc M, Pittock SJ, et al. Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing. JAMA Neurol. 2021;78(6):741-746. [Crossref]  [PubMed]  [PMC]
  71. Takai Y, Misu T, Kaneko K, et al. Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study. Brain. 2020;143(5):1431-1446. [Crossref]  [PubMed]
  72. Kim YC, Zhang A-H, Yoon J, et al. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J Autoimmun. 2018;92:77-86. [Crossref]  [PubMed]  [PMC]
  73. Hassani A, Corboy JR, Al-Salam S, Khan G. Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. PLoS One. 2018;13(2):e0192109. [Crossref]  [PubMed]  [PMC]
  74. Thorley-Lawson DA. Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol. 2001;1(1):75-82. [Crossref]  [PubMed]
  75. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. [Crossref]  [PubMed]
  76. Aloisi F, Giovannoni G, Salvetti M. Epstein-Barr virus as a cause of multiple sclerosis: opportunities for prevention and therapy. Lancet Neurol. 2023;22(4):338-349. [Crossref]  [PubMed]