Research progress on neuroinflammatory mechanisms of blood-brain barrier damage and repair in ischemic stroke_West China Medical Journal

Authors：

DU Renfeng ¹ , YU Bo ² , PAN Danhong ¹ , LIN Yanping ¹ , WANG Qinghua ¹ ,  LI Yongnan ³ ,  HOU Shuangxing ¹

1. Department of Neurology, Shanghai Pudong Hospital - Fudan University Pudong Medical Center, Shanghai 201399, P. R. China;
2. Department of Vascular Surgery, Shanghai Pudong Hospital - Fudan University Pudong Medical Center, Shanghai 201399, P. R. China;
3. Department of Neurology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P. R. China;

Corresponding author：

LI Yongnan, Email: yongnanli818@aliyun.com; HOU Shuangxing, Email: housx120@126.com

Keywords：

Ischemic stroke; blood-brain barrier; neuroinflammation; glial cells

DOI：

10.7507/1002-0179.202106277

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Ischemic stroke (IS) is one of the important diseases threatening human health. The occurrence and development of IS can trigger a series of complex pathophysiological changes, including damage to the blood-brain barrier, ion imbalance, oxidative stress, mitochondrial damage, which ultimately lead to the apoptosis and necrosis of nerve cells in the ischemic area. Impaired blood-brain barrier is a key factor for cerebral edema, hemorrhagic transformation and poor prognosis in patients with IS, and neuroinflammatory response plays an important role in the damage and repair of the blood-brain barrier. This article mainly focuses on the neuroinflammatory response mediated by glial cells, pro-inflammatory cytokines and matrix metalloproteinases and the related mechanisms of IS blood-brain barrier damage and repair, in order to provide new directions for the treatment of IS.

Citation： DU Renfeng, YU Bo, PAN Danhong, LIN Yanping, WANG Qinghua, LI Yongnan, HOU Shuangxing. Research progress on neuroinflammatory mechanisms of blood-brain barrier damage and repair in ischemic stroke. West China Medical Journal, 2022, 37(4): 622-626. doi: 10.7507/1002-0179.202106277 Copy

1.	Maida CD, Norrito RL, Daidone M, et al. Neuroinflammatory mechanisms in ischemic stroke: focus on cardioembolic stroke, background, and therapeutic approaches. Int J Mol Sci, 2020, 21(18): 6454.
2.	Kim JH, Kim SY, Kim B, et al. Prospects of therapeutic target and directions for ischemic stroke. Pharmaceuticals (Basel), 2021, 14(4): 321.
3.	Zhang W, Zhu L, An C, et al. The blood brain barrier in cerebral ischemic injury - disruption and repair. Brain Hemorrhages, 2020, 1(1): 34-53.
4.	Yang C, Hawkins KE, Doré S, et al. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol, 2019, 316(2): C135-C153.
5.	Bernardo-Castro S, Sousa JA, Brás A, et al. Pathophysiology of blood-brain barrier permeability throughout the different stages of ischemic stroke and its implication on hemorrhagic transformation and recovery. Front Neurol, 2020, 11: 594672.
6.	Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS, 2020, 17(1): 69.
7.	Xiao M, Xiao ZJ, Yang B, et al. Blood-brain barrier: more contributor to disruption of central nervous system homeostasis than victim in neurological disorders. Front Neurosci, 2020, 14: 764.
8.	Lochhead JJ, Yang J, Ronaldson PT, et al. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front Physiol, 2020, 11: 914.
9.	Patabendige A, Singh A, Jenkins S, et al. Astrocyte activation in neurovascular damage and repair following ischaemic stroke. Int J Mol Sci, 2021, 22(8): 4280.
10.	Chen Y, Qin C, Huang J, et al. The role of astrocytes in oxidative stress of central nervous system: a mixed blessing. Cell Prolif, 2020, 53(3): e12781.
11.	Malone K, Amu S, Moore AC, et al. Immunomodulatory therapeutic strategies in stroke. Front Pharmacol, 2019, 10: 630.
12.	Huang X, Hussain B, Chang J. Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms. CNS Neurosci Ther, 2021, 27(1): 36-47.
13.	Zhang W, Tian T, Gong SX, et al. Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke. Neural Regen Res, 2021, 16(1): 6-11.
14.	Jiang X, Andjelkovic AV, Zhu L, et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol, 2018(163/164): 144-171.
15.	Jayaraj RL, Azimullah S, Beiram R, et al. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation, 2019, 16(1): 142.
16.	Michinaga S, Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood-brain barrier function after brain damage. Int J Mol Sci, 2019, 20(3): 571.
17.	He X, Liu Y, Lin X, et al. Netrin-1 attenuates brain injury after middle cerebral artery occlusion via downregulation of astrocyte activation in mice. J Neuroinflammation, 2018, 15(1): 268.
18.	Begum G, Song S, Wang S, et al. Selective knockout of astrocytic Na⁺ /H⁺ exchanger isoform 1 reduces astrogliosis, BBB damage, infarction, and improves neurological function after ischemic stroke. Glia, 2018, 66(1): 126-144.
19.	Xu S, Lu J, Shao A, et al. Glial cells: role of the immune response in ischemic stroke. Front Immunol, 2020, 11: 294.
20.	Lu Y, Sareddy GR, Wang J, et al. Neuron-derived estrogen is critical for astrocyte activation and neuroprotection of the ischemic brain. J Neurosci, 2020, 40(38): 7355-7374.
21.	He J, Liu J, Huang Y, et al. Oxidative stress, inflammation, and autophagy: potential targets of mesenchymal stem cells-based therapies in ischemic stroke. Front Neurosci, 2021, 15: 641157.
22.	Hayakawa K, Esposito E, Wang X, et al. Corrigendum: transfer of mitochondria from astrocytes to neurons after stroke. Nature, 2016, 539(7627): 123.
23.	Hansen RB, Laursen CCH, Nawaz N, et al. Leukocyte TNFR1 and TNFR2 expression contributes to the peripheral immune response in cases with ischemic stroke. Cells, 2021, 10(4): 861.
24.	Huţanu A, Iancu M, Bălaşa R, et al. Predicting functional outcome of ischemic stroke patients in Romania based on plasma CRP, sTNFR-1, D-Dimers, NGAL and NSE measured using a biochip array. Acta Pharmacol Sin, 2018, 39(7): 1228-1236.
25.	Dabrowska S, Andrzejewska A, Lukomska B, et al. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation, 2019, 16(1): 178.
26.	Denes A, Wilkinson F, Bigger B, et al. Central and haematopoietic interleukin-1 both contribute to ischaemic brain injury in mice. Dis Model Mech, 2013, 6(4): 1043-1048.
27.	Wu MH, Huang CC, Chio CC, et al. Inhibition of peripheral TNF-α and downregulation of microglial activation by alpha-lipoic acid and etanercept protect rat brain against ischemic stroke. Mol Neurobiol, 2016, 53(7): 4961-4971.
28.	Chen AQ, Fang Z, Chen XL, et al. Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke. Cell Death Dis, 2019, 10(7): 487.
29.	Huang H, Huang Q, Wang F, et al. Cerebral ischemia-induced angiogenesis is dependent on tumor necrosis factor receptor 1-mediated upregulation of α5β1 and αVβ3 integrins. J Neuroinflammation, 2016, 13(1): 227.
30.	Wong R, Lénárt N, Hill L, et al. Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. Brain Behav Immun, 2019, 76: 126-138.
31.	McCulloch L, Allan SM, Emsley HC, et al. Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence. F1000Res, 2019, 8: 1039.
32.	Serhan A, Aerts JL, Boddeke EWGM, et al. Neuroprotection by insulin-like growth factor-1 in rats with ischemic stroke is associated with microglial changes and a reduction in neuroinflammation. Neuroscience, 2020, 426: 101-114.
33.	Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy?. Acta Neuropathol, 2019, 137(5): 693-714.
34.	Mengel A, Ulm L, Hotter B, et al. Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study. BMC Neurol, 2019, 19(1): 148.
35.	Li X, Lin S, Chen X, et al. The prognostic value of serum cytokines in patients with acute ischemic stroke. Aging Dis, 2019, 10(3): 544-556.
36.	Rochfort KD, Cummins PM. The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans, 2015, 43(4): 702-706.
37.	Caplan LR, Biller J, Leary MC, et al. Primer on Cerebrovascular Diseases//Ballesteros I, Cuartero MI, Pradillo J, et al. Amsterdam:Elsevier Besloten Vennootschap, 2017: 280-284.
38.	Feng Q, Wang YI, Yang Y. Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia. Exp Ther Med, 2015, 9(5): 1695-1701.
39.	Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res, 2015, 1623: 30-38.
40.	Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab, 2016, 36(9): 1481-1507.
41.	Mechtouff L, Bochaton T, Paccalet A, et al. Matrix metalloproteinase-9 relationship with infarct growth and hemorrhagic transformation in the era of thrombectomy. Front Neurol, 2020, 11: 473.
42.	Zhong C, Yang J, Xu T, et al. Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke. Neurology, 2017, 89(8): 805-812.
43.	Zhong C, Bu X, Xu T, et al. Serum matrix metalloproteinase-9 and cognitive impairment after acute ischemic stroke. J Am Heart Assoc, 2018, 7(1): e007776.
44.	Che B, Zhong C, Ge J, et al. Serum matrix metalloproteinase-9 is associated with depression after acute ischemic stroke. Circ J, 2019, 83(11): 2303-2311.
45.	Sheng Z, Liu Y, Li H, et al. Efficacy of minocycline in acute ischemic stroke: a systematic review and meta-analysis of rodent and clinical studies. Front Neurol, 2018, 9: 1103.
46.	Victoria ECG, Toscano ECB, Oliveira FMS, et al. Up-regulation of brain cytokines and metalloproteinases 1 and 2 contributes to neurological deficit and brain damage in transient ischemic stroke. Microvasc Res, 2020, 129: 103973.
47.	Montaner J, Ramiro L, Simats A, et al. Matrix metalloproteinases and ADAMs in stroke. Cell Mol Life Sci, 2019, 76(16): 3117-3140.
48.	Wójcik-Stanaszek L, Sypecka J, Szymczak P, et al. The potential role of metalloproteinases in neurogenesis in the gerbil hippocampus following global forebrain ischemia. PLoS One, 2011, 6(7): e22465.

1. Maida CD, Norrito RL, Daidone M, et al. Neuroinflammatory mechanisms in ischemic stroke: focus on cardioembolic stroke, background, and therapeutic approaches. Int J Mol Sci, 2020, 21(18): 6454.
2. Kim JH, Kim SY, Kim B, et al. Prospects of therapeutic target and directions for ischemic stroke. Pharmaceuticals (Basel), 2021, 14(4): 321.
3. Zhang W, Zhu L, An C, et al. The blood brain barrier in cerebral ischemic injury - disruption and repair. Brain Hemorrhages, 2020, 1(1): 34-53.
4. Yang C, Hawkins KE, Doré S, et al. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol, 2019, 316(2): C135-C153.
5. Bernardo-Castro S, Sousa JA, Brás A, et al. Pathophysiology of blood-brain barrier permeability throughout the different stages of ischemic stroke and its implication on hemorrhagic transformation and recovery. Front Neurol, 2020, 11: 594672.
6. Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS, 2020, 17(1): 69.
7. Xiao M, Xiao ZJ, Yang B, et al. Blood-brain barrier: more contributor to disruption of central nervous system homeostasis than victim in neurological disorders. Front Neurosci, 2020, 14: 764.
8. Lochhead JJ, Yang J, Ronaldson PT, et al. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front Physiol, 2020, 11: 914.
9. Patabendige A, Singh A, Jenkins S, et al. Astrocyte activation in neurovascular damage and repair following ischaemic stroke. Int J Mol Sci, 2021, 22(8): 4280.
10. Chen Y, Qin C, Huang J, et al. The role of astrocytes in oxidative stress of central nervous system: a mixed blessing. Cell Prolif, 2020, 53(3): e12781.
11. Malone K, Amu S, Moore AC, et al. Immunomodulatory therapeutic strategies in stroke. Front Pharmacol, 2019, 10: 630.
12. Huang X, Hussain B, Chang J. Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms. CNS Neurosci Ther, 2021, 27(1): 36-47.
13. Zhang W, Tian T, Gong SX, et al. Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke. Neural Regen Res, 2021, 16(1): 6-11.
14. Jiang X, Andjelkovic AV, Zhu L, et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol, 2018(163/164): 144-171.
15. Jayaraj RL, Azimullah S, Beiram R, et al. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation, 2019, 16(1): 142.
16. Michinaga S, Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood-brain barrier function after brain damage. Int J Mol Sci, 2019, 20(3): 571.
17. He X, Liu Y, Lin X, et al. Netrin-1 attenuates brain injury after middle cerebral artery occlusion via downregulation of astrocyte activation in mice. J Neuroinflammation, 2018, 15(1): 268.
18. Begum G, Song S, Wang S, et al. Selective knockout of astrocytic Na⁺ /H⁺ exchanger isoform 1 reduces astrogliosis, BBB damage, infarction, and improves neurological function after ischemic stroke. Glia, 2018, 66(1): 126-144.
19. Xu S, Lu J, Shao A, et al. Glial cells: role of the immune response in ischemic stroke. Front Immunol, 2020, 11: 294.
20. Lu Y, Sareddy GR, Wang J, et al. Neuron-derived estrogen is critical for astrocyte activation and neuroprotection of the ischemic brain. J Neurosci, 2020, 40(38): 7355-7374.
21. He J, Liu J, Huang Y, et al. Oxidative stress, inflammation, and autophagy: potential targets of mesenchymal stem cells-based therapies in ischemic stroke. Front Neurosci, 2021, 15: 641157.
22. Hayakawa K, Esposito E, Wang X, et al. Corrigendum: transfer of mitochondria from astrocytes to neurons after stroke. Nature, 2016, 539(7627): 123.
23. Hansen RB, Laursen CCH, Nawaz N, et al. Leukocyte TNFR1 and TNFR2 expression contributes to the peripheral immune response in cases with ischemic stroke. Cells, 2021, 10(4): 861.
24. Huţanu A, Iancu M, Bălaşa R, et al. Predicting functional outcome of ischemic stroke patients in Romania based on plasma CRP, sTNFR-1, D-Dimers, NGAL and NSE measured using a biochip array. Acta Pharmacol Sin, 2018, 39(7): 1228-1236.
25. Dabrowska S, Andrzejewska A, Lukomska B, et al. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation, 2019, 16(1): 178.
26. Denes A, Wilkinson F, Bigger B, et al. Central and haematopoietic interleukin-1 both contribute to ischaemic brain injury in mice. Dis Model Mech, 2013, 6(4): 1043-1048.
27. Wu MH, Huang CC, Chio CC, et al. Inhibition of peripheral TNF-α and downregulation of microglial activation by alpha-lipoic acid and etanercept protect rat brain against ischemic stroke. Mol Neurobiol, 2016, 53(7): 4961-4971.
28. Chen AQ, Fang Z, Chen XL, et al. Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke. Cell Death Dis, 2019, 10(7): 487.
29. Huang H, Huang Q, Wang F, et al. Cerebral ischemia-induced angiogenesis is dependent on tumor necrosis factor receptor 1-mediated upregulation of α5β1 and αVβ3 integrins. J Neuroinflammation, 2016, 13(1): 227.
30. Wong R, Lénárt N, Hill L, et al. Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. Brain Behav Immun, 2019, 76: 126-138.
31. McCulloch L, Allan SM, Emsley HC, et al. Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence. F1000Res, 2019, 8: 1039.
32. Serhan A, Aerts JL, Boddeke EWGM, et al. Neuroprotection by insulin-like growth factor-1 in rats with ischemic stroke is associated with microglial changes and a reduction in neuroinflammation. Neuroscience, 2020, 426: 101-114.
33. Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy?. Acta Neuropathol, 2019, 137(5): 693-714.
34. Mengel A, Ulm L, Hotter B, et al. Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study. BMC Neurol, 2019, 19(1): 148.
35. Li X, Lin S, Chen X, et al. The prognostic value of serum cytokines in patients with acute ischemic stroke. Aging Dis, 2019, 10(3): 544-556.
36. Rochfort KD, Cummins PM. The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans, 2015, 43(4): 702-706.
37. Caplan LR, Biller J, Leary MC, et al. Primer on Cerebrovascular Diseases//Ballesteros I, Cuartero MI, Pradillo J, et al. Amsterdam:Elsevier Besloten Vennootschap, 2017: 280-284.
38. Feng Q, Wang YI, Yang Y. Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia. Exp Ther Med, 2015, 9(5): 1695-1701.
39. Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res, 2015, 1623: 30-38.
40. Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab, 2016, 36(9): 1481-1507.
41. Mechtouff L, Bochaton T, Paccalet A, et al. Matrix metalloproteinase-9 relationship with infarct growth and hemorrhagic transformation in the era of thrombectomy. Front Neurol, 2020, 11: 473.
42. Zhong C, Yang J, Xu T, et al. Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke. Neurology, 2017, 89(8): 805-812.
43. Zhong C, Bu X, Xu T, et al. Serum matrix metalloproteinase-9 and cognitive impairment after acute ischemic stroke. J Am Heart Assoc, 2018, 7(1): e007776.
44. Che B, Zhong C, Ge J, et al. Serum matrix metalloproteinase-9 is associated with depression after acute ischemic stroke. Circ J, 2019, 83(11): 2303-2311.
45. Sheng Z, Liu Y, Li H, et al. Efficacy of minocycline in acute ischemic stroke: a systematic review and meta-analysis of rodent and clinical studies. Front Neurol, 2018, 9: 1103.
46. Victoria ECG, Toscano ECB, Oliveira FMS, et al. Up-regulation of brain cytokines and metalloproteinases 1 and 2 contributes to neurological deficit and brain damage in transient ischemic stroke. Microvasc Res, 2020, 129: 103973.
47. Montaner J, Ramiro L, Simats A, et al. Matrix metalloproteinases and ADAMs in stroke. Cell Mol Life Sci, 2019, 76(16): 3117-3140.
48. Wójcik-Stanaszek L, Sypecka J, Szymczak P, et al. The potential role of metalloproteinases in neurogenesis in the gerbil hippocampus following global forebrain ischemia. PLoS One, 2011, 6(7): e22465.

West China Medical Journal

Research progress on neuroinflammatory mechanisms of blood-brain barrier damage and repair in ischemic stroke

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content