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Cytokines and subarachnoid hemorrhage

FNU Ruchika, Siddharth Shah, Maliya Delawan, Neupane Durga, Brandon Lucke-Wold

Abstract

Subarachnoid hemorrhage (SAH) remains a potentially devastating cerebrovascular disease with a high morbidity and mortality rate, irrespective of treatment. The disease still has a 40-50% mortality rate with a 70% rate of cerebral vasospasm in those patients. The release of cytokines has been implicated in the development and progression of SAH. In this paper, we will explore the role of cytokines in aneurysmal subarachnoid hemorrhage (aSAH), including their effects on the inflammatory response, cerebral vasospasm, blood-brain barrier disruption, and neuronal damage. We also identify the role of the glymphatic system in progression of aSAH. The review will also briefly touch upon current research on potential therapeutic targets aimed at modulating cytokine activity in patients with aSAH. This review aims to give an in-depth review of the cytokines involved in aSAH and serve as a catalyst to research directed towards treatment options for aSAH.


Keywords

subarachnoid hemorrhage; cytokines; inflammation; TNF-α; interleukin; secondary brain injury

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References

1. Budohoski KP, Guilfoyle M, Helmy A, et al. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. Journal of Neurology, Neurosurgery & Psychiatry 2014; 85(12): 1343–1353. doi: 10.1136/jnnp-2014-307711

2. Dodd WS, Laurent D, Dumont AS, et al. Pathophysiology of delayed cerebral ischemia after subarachnoid hemorrhage: A review. Journal of the American Heart Association 2021; 10(15): e021845. doi: 10.1161/JAHA.121.021845

3. Stoll JR, Vaidya TS, Mori S, et al. Association of interleukin-6 and tumor necrosis factor-α with mortality in hospitalized patients with cancer. Journal of the American Academy of Dermatology 2021; 84(2): 273–282. doi: 10.1016/j.jaad.2020.03.010

4. Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Experimental & Molecular Medicine 2021; 53(7): 1116–1123. doi: 10.1038/s12276-021-00649-0

5. Rochfort KD, Collins LE, McLoughlin A, Cummins PM. Tumour necrosis factor-α-mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin-6. Journal of Neurochemistry 2016; 136(3): 564–572. doi: 10.1111/jnc.13408

6. Bauer AM, Rasmussen PA. Treatment of intracranial vasospasm following subarachnoid hemorrhage. Frontiers in Neurology 2014; 5: 72. doi: 10.3389/fneur.2014.00072

7. Geraghty JR, Testai FD. Delayed cerebral ischemia after subarachnoid hemorrhage: Beyond vasospasm and towards a multifactorial pathophysiology. Current Atherosclerosis Reports 2017; 19(12): 50. doi: 10.1007/s11883-017-0690-x

8. Dong G, Li C, Hu Q, et al. Low-dose IL-2 treatment affords protection against subarachnoid hemorrhage injury by expanding peripheral regulatory T cells. ACS Chemical Neuroscience 2021; 12(3): 430–440. doi: 10.1021/acschemneuro.0c00611

9. Chen S, Xu PL, Fang Y, Lenahan C. The updated role of the blood brain barrier in subarachnoid hemorrhage: From basic and clinical studies. Current Neuropharmacology 2020; 18(12): 1266–1278. doi: 10.2174/1570159X18666200914161231

10. Theofilis P, Sagris M, Oikonomou E, et al. Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines 2021; 9(7): 781. doi: 10.3390/biomedicines9070781

11. Aoki T, Frȍsen J, Fukuda M, et al. Prostaglandin E2-EP2-NF-κB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. Science Signaling 2017; 10(465): eaah6037. doi: 10.1126/scisignal.aah6037

12. Frösen J, Cebral J, Robertson AM, Aoki T. Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms. Neurosurgical Focus 2019; 47(1): E21. doi: 10.3171/2019.5.focus19234

13. Lucke-Wold BP, Logsdon AF, Manoranjan B, et al. Aneurysmal subarachnoid hemorrhage and neuroinflammation: A comprehensive review. International Journal of Molecular Sciences 2016; 17(4): 497. doi: 10.3390/ijms17040497

14. Weiland J, Beez A, Westermaier T, et al. Neuroprotective strategies in aneurysmal subarachnoid hemorrhage (aSAH). International Journal of Molecular Sciences. 2021; 22(11): 5442. doi: 10.3390/ijms22115442

15. Li K, Barras CD, Chandra RV, et al. A review of the management of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. World Neurosurgery 2019; 126: 513–527. doi: 10.1016/j.wneu.2019.03.083

16. Viderman D, Tapinova K, Abdildin YG. Mechanisms of cerebral vasospasm and cerebral ischaemia in subarachnoid haemorrhage. Clinical Physiology and Functional Imaging 2023; 43(1): 1–9. doi: 10.1111/cpf.12787

17. Al-Tamimi YZ, Bhargava D, Orsi NM, et al. Compartmentalisation of the inflammatory response following aneurysmal subarachnoid haemorrhage. Cytokine 2019; 123: 154778. doi: 10.1016/j.cyto.2019.154778

18. Fassbender K, Hodapp B, Rossol S, et al. Inflammatory cytokines in subarachnoid haemorrhage: Association with abnormal blood flow velocities in basal cerebral arteries. Journal of Neurology, Neurosurgery & Psychiatry 2001; 70(4): 534–537. doi: 10.1136/jnnp.70.4.534

19. Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH. Neuroendocrinology Letters 2004; 25(1–2): 141–147.

20. Jedrzejowska-Szypułka H, Larysz-Brysz M, Kukla M, et al. Neutralization of interleukin-1beta reduces vasospasm and alters cerebral blood vessel density following experimental subarachnoid hemorrhage in rats. Current Neurovascular Research 2009; 6(2): 95–103. doi: 10.2174/156720209788185669

21. Croci DM, Sivanrupan S, Wanderer S, et al. Preclinical and clinical role of interleukin-6 in the development of delayed cerebral vasospasm and neuronal cell death after subarachnoid hemorrhage: Towards a potential target therapy? Neurosurgical Review 2022; 45(1): 395–403. doi: 10.1007/s10143-021-01628-9

22. Osuka K, Suzuki Y, Tanazawa T, et al. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochirurgica 1998; 140(9): 943–951. doi: 10.1007/s007010050197

23. Chaudhry SR, Stoffel-Wagner B, Kinfe TM, et al. Elevated systemic IL-6 levels in patients with aneurysmal subarachnoid hemorrhage is an unspecific marker for post-SAH complications. International Journal of Molecular Sciences 2017; 18(12): 2580. doi: 10.3390/ijms18122580

24. Liu W, Li R, Yin J, et al. Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: Involvement of botch. Journal of Neuroinflammation. 2019; 16: 1–20. doi: 10.1186/s12974-019-1396-5

25. Wang Y, Zhong M, Tan XX, et al. Expression change of interleukin-8 gene in rabbit basilar artery after subarachnoid hemorrhage. Neuroscience Bulletin 2007; 23(3): 151–155. doi: 10.1007/s12264-007-0022-1

26. Griessenauer CJ, Chua MH, Hanafy KA, et al. Soluble Fms-like tyrosine kinase 1 (sFlt-1) and risk of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. World Neurosurgery 2017; 108: 84–89. doi: 10.1016/j.wneu.2017.08.128

27. Ahn SH, Burkett A, Paz A, et al. Systemic inflammatory markers of persistent cerebral edema after aneurysmal subarachnoid hemorrhage. Journal of Neuroinflammation 2022; 19(1): 199. doi: 10.1186/s12974-022-02564-1

28. Vlachogiannis P, Hillered L, Enblad P, Ronne-Engström E. Temporal patterns of inflammation-related proteins measured in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage using multiplex proximity extension assay technology. PLoS One 2022; 17(3): e0263460. doi: 10.1371/journal.pone.0263460

29. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews 2005; 57(2): 173–185. doi: 10.1124/pr.57.2.4

30. Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: Molecular organization and role in vascular homeostasis. Physiological Reviews 2004; 84(3): 869–901. doi: 10.1152/physrev.00035.2003

31. Walsh TG, Murphy RP, Fitzpatrick P, et al. Stabilization of brain microvascular endothelial barrier function by shear stress involves VE‐cadherin signaling leading to modulation of pTyr‐occludin levels. Journal of Cellular Physiology 2011; 226(11): 3053–3063. doi: 10.1002/jcp.22655

32. Alves JL. Blood-brain barrier and traumatic brain injury. Journal of Neuroscience Research 2014; 92(2): 141–147. doi: 10.1002/jnr.23300

33. Geraghty JR, Davis JL, Testai FD. Neuroinflammation and microvascular dysfunction after experimental subarachnoid hemorrhage: Emerging components of early brain injury related to outcome. Neurocritical Care 2019; 31(2): 373–389. doi: 10.1007/s12028-019-00710-x

34. Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. American Journal of Physiology-Cell Physiology 2019; 316(2): C135–C153. doi: 10.1152/ajpcell.00136.2018.

35. Zhao Y, Luo Y, Liu Y, et al. The role of autophagy and apoptosis in early brain injury after subarachnoid hemorrhage: An updated review. Molecular biology reports 2022; 49(11): 10775–10782. doi: 10.1007/s11033-022-07756-9

36. Figiel I. Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain. Acta Neurobiologiae Experimentalis 2008; 68(4): 526–534.

37. Lopez-Ramirez MA, Fischer R, Torres-Badillo CC, et al. Role of caspases in cytokine-induced barrier breakdown in human brain endothelial cells. The Journal of Immunology 2012; 189(6): 3130–3139. doi: 10.4049/jimmunol.1103460

38. Nishioku T, Matsumoto J, Dohgu S, et al. Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. Journal of Pharmacological Sciences 2010; 112(2): 251–254. doi: 10.1254/jphs.09292sc

39. Lad SP, Hegen H, Gupta G, et al. Proteomic biomarker discovery in cerebrospinal fluid for cerebral vasospasm following subarachnoid hemorrhage. Journal of Stroke and Cerebrovascular Diseases 2012; 21(1): 30–41. doi: 10.1016/j.jstrokecerebrovasdis.2010.04.004

40. Wang JW, Gao JM, Huang YJ. Effects of puerarin on the vascular active factor related to cerebral vasospasm after aneurysm subarachnoid hemorrhage. Chinese Journal of Integrated Traditional and Western Medicine 2012; 32(2): 164–167.

41. Aslam M, Ahmad N, Srivastava R, Hemmer B. TNF-alpha induced NFκB signaling and p65 (RelA) overexpression repress Cldn5 promoter in mouse brain endothelial cells. Cytokine 2012; 57(2): 269–275. doi: 10.1016/j.cyto.2011.10.016

42. Goulay R, Flament J, Gauberti M, et al. Subarachnoid hemorrhage severely impairs brain parenchymal cerebrospinal fluid circulation in nonhuman primate. Stroke 2017; 48(8): 2301–2305. doi: 10.1161/STROKEAHA.117.017014

43. Pluta RM, Bacher J, Skopets B, Hoffmann V. A non-human primate model of aneurismal subarachnoid hemorrhage (SAH). Translational Stroke Research 2014; 5(6): 681–691. doi: 10.1007/s12975-014-0371-9

44. Luo C, Yao X, Li J, et al. Paravascular pathways contribute to vasculitis and neuroinflammation after subarachnoid hemorrhage independently of glymphatic control. Cell Death & Disease 2016; 7(3): e2160. doi: 10.1038/cddis.2016.63

45. Lv T, Zhao B, Hu Q, Zhang X. The glymphatic system: A novel therapeutic target for stroke treatment. Frontiers in Aging Neuroscience 2021; 13: 689098. doi: 10.3389/fnagi.2021.689098

46. Boluijt J, Meijers JCM, Rinkel GJE, Vergouwen MDI. Hemostasis and fibrinolysis in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: A systematic review. Journal of Cerebral Blood Flow & Metabolism 2015; 35(5): 724–733. doi: 10.1038/jcbfm.2015.13

47. Ren Z, Iliff JJ, Yang L, et al. ‘Hit & run’ model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. Journal of Cerebral Blood Flow & Metabolism 2013; 33(6): 834–845. doi: 10.1038/jcbfm.2013.30

48. Liu E, Peng X, Ma H, et al. The involvement of aquaporin-4 in the interstitial fluid drainage impairment following subarachnoid hemorrhage. Frontiers in Aging Neuroscience 2021; 12: 611494. doi: 10.3389/fnagi.2020.611494

49. Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage. Stroke 2012; 43(6): 1711–1737. doi: 10.1161/STR.0b013e3182587839

50. Dayyani M, Sadeghirad B, Grotta JC, et al. Prophylactic therapies for morbidity and mortality after aneurysmal subarachnoid hemorrhage: A systematic review and network meta-analysis of randomized trials. Stroke 2022; 53(6): 1993–2005. doi: 10.1161/STROKEAHA.121.035699

51. Hong Y, He S, Zou Q, et al. Eupatilin alleviates inflammatory response after subarachnoid hemorrhage by inhibition of TLR4/MyD88/NF-κB axis. Journal of Biochemical and Molecular Toxicology 2023; 37(5): e23317. doi: 10.1002/jbt.23317

52. Galea J, Ogungbenro K, Hulme S, et al. Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: Results of the subcutaneous interleukin-1Ra in SAH (SCIL-SAH) study. Journal of Neurosurgery 2018; 128(2): 515–523. doi: 10.3171/2016.9.JNS16615

53. Zuo T, Gong B, Gao Y, Yuan L. An in vitro study on the stimulatory effects of extracellular glutamate on astrocytes. Molecular Biology Reports 2023; 50(8): 6611–6617. doi: 10.1007/s11033-023-08601-3

54. Yang LY, Chen YR, Lee JE, et al. Dental pulp stem cell-derived conditioned medium alleviates subarachnoid hemorrhage-induced microcirculation impairment by promoting M2 microglia polarization and reducing astrocyte swelling. Translational Stroke Research 2022; 14(5): 688–703. doi: 10.1007/s12975-022-01083-8

55. Chung C, Tsai H, Huang Y, et al. Attenuation in proinflammatory factors and reduction in neuronal cell apoptosis and cerebral vasospasm by minocycline during early phase after subarachnoid hemorrhage in the rat. BioMed Research International 2021; 2021: 5545727. doi: 10.1155/2021/5545727

56. Jiang Y, Liu DW, Han XY, et al. Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model. Journal of Clinical Neuroscience 2012; 19(6): 866–872. doi: 10.1016/j.jocn.2011.08.038

57. Maddahi A, Povlsen GK, Edvinsson L. Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. Journal of Neuroinflammation 2012; 9(1): 274. doi: 10.1186/1742-2094-9-274

58. Sun X, Ji C, Hu T, et al. Tamoxifen as an effective neuroprotectant against early brain injury and learning deficits induced by subarachnoid hemorrhage: Possible involvement of inflammatory signaling. Journal of Neuroinflammation 2013; 10(1): 920. doi: 10.1186/1742-2094-10-157

59. Wang Y, Zhou S, Han Z, et al. Fingolimod administration improves neurological functions of mice with subarachnoid hemorrhage. Neuroscience Letters 2020; 736: 135250. doi: 10.1016/j.neulet.2020.135250

60. Xu H, Testai FD, Valyi-Nagy T, et al. VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism. Brain Research 2015; 1603: 141–149. doi: 10.1016/j.brainres.2015.01.047

61. Xu H, Pelligrino DA, Paisansathan C, Testai FD. Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage. Journal of Neuroinflammation. 2015; 12(1): 16. doi: 10.1186/s12974-015-0234-7.

62. Chen J, Chen G, Li J, et al. Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: A possible role for the regulation of pro-inflammatory cytokines. Journal of Pineal Research 2014; 57(3): 340–347. doi: 10.1111/jpi.12173

63. Lin CL, Dumont AS, Calisaneller T, et al. Monoclonal antibody against E selectin attenuates subarachnoid hemorrhage-induced cerebral vasospasm. Surgical Neurology 2005; 64(3): 201–205. doi: 10.1016/j.surneu.2005.04.038

64. Pradilla G, Wang PP, Legnani FG, et al. Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. Journal of Neurosurgery 2004; 101(1): 88–92. doi: 10.3171/jns.2004.101.1.0088

65. Provencio JJ, Altay T, Smithason S, et al. Depletion of Ly6G/C+ cells ameliorates delayed cerebral vasospasm in subarachnoid hemorrhage. Journal of Neuroimmunology 2011; 232(1–2): 94–100. doi: 10.1016/j.jneuroim.2010.10.016

66. Wu Y, Zhao X, Zhuang Z, et al. Peroxisome proliferator-activated receptor gamma agonist rosiglitazone attenuates oxyhemoglobin-induced toll-like receptor 4 expression in vascular smooth muscle cells. Brain Research 2010; 1322: 102–108. doi: 10.1016/j.brainres.2010.01.073

67. Yang WS, Jeng CY, Wu TJ, et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002; 25(2): 376–380. doi: 10.2337/diacare.25.2.376.

68. Tosun C, Kurland DB, Mehta R, et al. Inhibition of the Sur1-Trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage. Stroke 2013; 44(12): 3522–3528. doi: 10.1161/STROKEAHA.113.002904

69. Shiokawa R, Otani N, Kajimoto R, et al. Glibenclamide attenuates brain edema associated with microglia activation after intracerebral hemorrhage. Neurochirurgie 2022; 68(6): 589–594. doi: 10.1016/j.neuchi.2022.07.009

70. Simon M, Grote A. Interleukin 6 and aneurysmal subarachnoid hemorrhage: A narrative review. International Journal of Molecular Sciences 2021; 22(8): 4133. doi: 10.3390/ijms22084133


DOI: https://doi.org/10.59400/ivd.v3i1.55
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