NEUROINFLAMMATION MECHANISMS, CLINICAL IMPLICATIONS, AND THERAPEUTIC APPROACHES

neuroinflamationkapak

NEUROINFLAMMATION IN STROKE: BENEFITS AND HARMS

Bijen Nazlıel1 Hale Zeynep Batur Çağlayan2 Taylan Altıparmak3

1Gazi University, Faculty of Medicine, Department of Neurology, Ankara, Türkiye
2Gazi University, Faculty of Medicine, Department of Neurology, Ankara, Türkiye
3Gazi University, Faculty of Medicine, Department of Neurology, Ankara, Türkiye

Nazlıel B, Batur Çağlayan HZ, Altıparmak T. Neuroinflammation in Stroke: Benefits and Harms. In: Şahin Ş editor. Neuroinflammation. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.37-47.

ABSTRACT

Neuroinflammation is a central component of the pathophysiological processes in ischemic and hemorrhagic strokes, spanning from the acute phase to the chronic stage through diverse cellular and molecular mechanisms. Microglial activation, cytokine expression, and immune cell infiltration constitute the core elements of the inflammatory response. While inflammation in the early phase leads to bloodbrain barrier disruption and neuronal loss, it supports angiogenesis and neuroregeneration in later stages. Targeting the temporal dynamics and cellular components of neuroinflammation holds significant potential for neuroprotective and neurorestorative strategies. Understanding the molecular regulators and immune modulation mechanisms may pave the way for novel translational research opportunities.

Keywords: Inflammation; Inflammation mediators; Ischemic stroke; Hemorrhagic stroke; Neuroinflammation

Referanslar

  1. Alsbrook DL, Di Napoli M, Bhatia K, et al. Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke. Curr Neurol Neurosci Rep. 2023;23(8):407-431. [Crossref]  [PubMed]  [PMC]
  2. Collaborators GBDSRF. Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024;23(10):973-1003. [Crossref]  [PubMed]
  3. Lanas F, Seron P. Facing the stroke burden worldwide. The Lancet Global Health. 2021;9(3):e235-e236. [Crossref]  [PubMed]
  4. Feigin VL, Owolabi MO, World Stroke Organization-Lancet Neurology Commission Stroke Collaboration G. Pragmatic solutions to reduce the global burden of stroke: a World Stroke Organization-Lancet Neurology Commission. Lancet Neurol. 2023;22(12):1160-1206. [Crossref]  [PMC]
  5. Boltze J, Perez-Pinzon MA. Focused Update on Stroke Neuroimmunology: Current Progress in Preclinical and Clinical Research and Recent Mechanistic Insight. Stroke. 2022;53(5):1432-1437. [Crossref]  [PubMed]
  6. Kumari S, Dhapola R, Sharma P, et al. The impact of cytokines in neuroinflammation-mediated stroke. Cytokine Growth Factor Rev. 2024;78:105-119. [Crossref]  [PubMed]
  7. Anthony S, Cabantan D, Monsour M, et al. Neuroinflammation, Stem Cells, and Stroke. Stroke. 2022;53(5):1460-1472. [Crossref]  [PubMed]  [PMC]
  8. Candelario-Jalil E, Dijkhuizen RM, Magnus T. Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities. Stroke. 2022;53(5):1473-1486. [Crossref]  [PubMed]  [PMC]
  9. Choi YH, Laaker C, Hsu M, et al. Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke. Int J Mol Sci. 2021;22(17). [Crossref]  [PubMed]  [PMC]
  10. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57(2):173-185. [Crossref]  [PubMed]
  11. Yang C, Hawkins KE, Dore S, et al. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019;316(2):C135-C153. [Crossref]  [PubMed]  [PMC]
  12. Gursoy-Ozdemir Y, Can A, Dalkara T. Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke. 2004;35(6):1449-1453. [Crossref]  [PubMed]
  13. Huang Z, Huang PL, Ma J, et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by ni tro-L-arginine. J Cereb Blood Flow Metab. 1996;16(5):981987. [Crossref]  [PubMed]
  14. Abdullahi W, Tripathi D, Ronaldson PT. Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol. 2018;315(3):C343-C356. [Crossref]  [PubMed]  [PMC]
  15. Li XH, Yin FT, Zhou XH, et al. The Signaling Pathways and Targets of Natural Compounds from Traditional Chinese Medicine in Treating Ischemic Stroke. Molecules. 2022;27(10). [Crossref]  [PubMed]  [PMC]
  16. Montaner J, Molina CA, Monasterio J, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107(4):598-603. [Crossref]  [PubMed]
  17. Ji Y, Gao Q, Ma Y, et al. An MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity. Pharmacol Res. 2023;190:106720. [Crossref]  [PubMed]  [PMC]
  18. Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci. 2020;21(3):139-152. [Crossref]  [PubMed]
  19. Xu S, Lu J, Shao A, et al. Glial Cells: Role of the Immune Response in Ischemic Stroke. Front Immunol. 2020;11:294. [Crossref]  [PubMed]  [PMC]
  20. Pascual M, Calvo-Rodriguez M, Nunez L, et al. Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage. IUBMB Life. 2021;73(7):900915. [Crossref]  [PubMed]
  21. Gulke E, Gelderblom M, Magnus T. Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Disord. 2018;11:1756286418774254. [Crossref]  [PubMed]  [PMC]
  22. Bsibsi M, Ravid R, Gveric D, et al. Broad expression of Tolllike receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61(11):1013-1021. [Crossref]  [PubMed]
  23. Kim E, Cho S. Microglia and Monocyte-Derived Macrophages in Stroke. Neurotherapeutics. 2016;13(4):702-718. [Crossref]  [PubMed]  [PMC]
  24. Srivastava A, Srivastava P, Verma R. Role of bone marrow-derived macrophages (BMDMs) in neurovascular interactions during stroke. Neurochem Int. 2019;129:104480. [Crossref]  [PubMed]
  25. Qiu YM, Zhang CL, Chen AQ, et al. Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy? Front Immunol. 2021;12:678744. [Crossref]  [PubMed]  [PMC]
  26. Dong X, Zhang X, Li C, et al. gammadelta T cells aggravate blood-brain-barrier injury via IL-17A in experimental ischemic stroke. Neurosci Lett. 2022;776:136563. [Crossref]  [PubMed]
  27. Ma Y, Yang S, He Q, et al. The Role of Immune Cells in PostStroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown. Front Immunol. 2021;12:784098. [Crossref]  [PubMed]  [PMC]
  28. Qin C, Zhou LQ, Ma XT, et al. Dual Functions of Microglia in Ischemic Stroke. Neurosci Bull. 2019;35(5):921-933. [Crossref]  [PubMed]  [PMC]
  29. Yenari MA, Xu L, Tang XN, et al. Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke. 2006;37(4):10871093. [Crossref]  [PubMed]
  30. Arunachalam P, Ludewig P, Melich P, et al. CCR6 (CC Chemokine Receptor 6) Is Essential for the Migration of Detrimental Natural Interleukin-17-Producing gammadelta T Cells in Stroke. Stroke. 2017;48(7):1957-1965. [Crossref]  [PubMed]
  31. Swardfager W, Winer DA, Herrmann N, et al. Interleukin-17 in post-stroke neurodegeneration. Neurosci Biobehav Rev. 2013;37(3):436-447. [Crossref]  [PubMed]
  32. McCann SK, Cramond F, Macleod MR, et al. Systematic Review and Meta-Analysis of the Efficacy of Interleukin-1 Receptor Antagonist in Animal Models of Stroke: an Update. Transl Stroke Res. 2016;7(5):395-406. [Crossref]  [PubMed]  [PMC]
  33. Smith CJ, Hulme S, Vail A, et al. SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial. Stroke. 2018;49(5):1210-1216. [Crossref]  [PubMed]
  34. Tambuyzer BR, Ponsaerts P, Nouwen EJ. Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol. 2009;85(3):352-370. [Crossref]  [PubMed]
  35. Dotson AL, Wang J, Saugstad J, et al. Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke. J Neuroimmunol. 2015;278:289-298. [Crossref]  [PubMed]  [PMC]
  36. Fumagalli S, Perego C, Pischiutta F, et al. The ischemic environment drives microglia and macrophage function. Front Neurol. 2015;6:81. [Crossref]  [PubMed]  [PMC]
  37. Ransohoff RM, Cardona AE. The myeloid cells of the central nervous system parenchyma. Nature. 2010;468(7321):253-262. [Crossref]  [PubMed]
  38. Kadl A, Meher AK, Sharma PR, et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res. 2010;107(6):737746. [Crossref]  [PubMed]  [PMC]
  39. Zhang R, Miao T, Qin M, et al. CX(3)CL1 Recruits NK Cells Into the Central Nervous System and Aggravates Brain Injury of Mice Caused by Angiostrongylus cantonensis Infection. Front Cell Infect Microbiol. 2021;11:672720. [Crossref]  [PubMed]  [PMC]
  40. Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. Mast cells as early responders in the regulation of acute bloodbrain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab. 2010;30(4):689-702. [Crossref]  [PubMed]  [PMC]
  41. De Meyer SF, Langhauser F, Haupeltshofer S, et al. Thromboinflammation in Brain Ischemia: Recent Updates and Future Perspectives. Stroke. 2022;53(5):1487-1499. [Crossref]  [PubMed]
  42. Kleinschnitz C, De Meyer SF, Schwarz T, et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood. 2009;113(15):3600-3603. [Crossref]  [PubMed]
  43. Zhao BQ, Chauhan AK, Canault M, et al. von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood. 2009;114(15):33293334. [Crossref]  [PubMed]  [PMC]
  44. Gob E, Reymann S, Langhauser F, et al. Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation. Ann Neurol. 2015;77(5):784-803. [Crossref]  [PubMed]
  45. Austinat M, Braeuninger S, Pesquero JB, et al. Blockade of bradykinin receptor B1 but not bradykinin receptor B2 provides protection from cerebral infarction and brain edema. Stroke. 2009;40(1):285-293. [Crossref]  [PubMed]
  46. Denorme F, Portier I, Rustad JL, et al. Neutrophil extracellular traps regulate ischemic stroke brain injury. J Clin Invest. 2022;132(10). [Crossref]  [PubMed]  [PMC]
  47. Gurler G, Soylu KO, Yemisci M. Importance of Pericytes in the Pathophysiology of Cerebral Ischemia. Noro Psikiyatr Ars. 2022;59(Suppl 1):S29-S35. [Crossref]  [PubMed]  [PMC]
  48. Rustenhoven J, Jansson D, Smyth LC, et al. Brain Pericytes As Mediators of Neuroinflammation. Trends Pharmacol Sci. 2017;38(3):291-304. [Crossref]  [PubMed]
  49. Armulik A, Genove G, Mae M, et al. Pericytes regulate the blood-brain barrier. Nature. 2010;468(7323):557-561. [Crossref]  [PubMed]
  50. Liesz A, Hu X, Kleinschnitz C, et al. Functional role of regulatory lymphocytes in stroke: facts and controversies. Stroke. 2015;46(5):1422-1430. [Crossref]  [PubMed]  [PMC]
  51. Ribeiro M, Brigas HC, Temido-Ferreira M, et al. Meningeal gammadelta T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019;4(40). [Crossref]  [PubMed]  [PMC]
  52. Ohashi SN, DeLong JH, Kozberg MG, et al. Role of Inflammatory Processes in Hemorrhagic Stroke. Stroke. 2023;54(2):605-619. [Crossref]  [PubMed]
  53. Nagy L, Szanto A, Szatmari I, et al. Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol Rev. 2012;92(2):739-789. [Crossref]  [PubMed]
  54. Hammond MD, Taylor RA, Mullen MT, et al. CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci. 2014;34(11):3901-3909. [Crossref]  [PubMed]  [PMC]
  55. Chang CF, Goods BA, Askenase MH, et al. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest. 2018;128(2):607-624. [Crossref]  [PubMed]  [PMC]
  56. Liu J, Zhang S, Jing Y, et al. Neutrophil extracellular traps in intracerebral hemorrhage: implications for pathogenesis and therapeutic targets. Metab Brain Dis. 2023;38(8):2505-2520. [Crossref]  [PubMed]
  57. Zhao X, Ting SM, Sun G, et al. Beneficial Role of Neutrophils Through Function of Lactoferrin After Intracerebral Hemorrhage. Stroke. 2018;49(5):1241-1247. [Crossref]  [PubMed]  [PMC]
  58. Klebe D, McBride D, Flores JJ, et al. Modulating the Immune Response Towards a Neuroregenerative Peri-injury Milieu After Cerebral Hemorrhage. J Neuroimmune Pharmacol. 2015;10(4):576-586. [Crossref]  [PubMed]  [PMC]
  59. Tschoe C, Bushnell CD, Duncan PW, et al. Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets. J Stroke. 2020;22(1):29-46. [Crossref]  [PubMed]  [PMC]
  60. Zhong Q, Zhou K, Liang QL, et al. Interleukin-23 Secreted by Activated Macrophages Drives gammadeltaT Cell Production of Interleukin-17 to Aggravate Secondary Injury After Intracerebral Hemorrhage. J Am Heart Assoc. 2016;5(10). [Crossref]  [PubMed]  [PMC]
  61. Shang Y, Zheng L, Du Y, et al. Role of Regulatory T Cells in Intracerebral Hemorrhage. Mol Neurobiol. 2024. [Crossref]  [PubMed]