Interleukin-6 Mediates Enhanced Thrombus Development in Cerebral Arterioles Following a Brief Period of Focal Brain Ischemia

Overview

Journal Exp Neurol

Specialty Neurology

Date 2015 Jun 10

PMID 26054883

Citations 11

Authors

Ya Hui Tang

Shantel Vital

Janice Russell

Hilary Seifert

D Neil Granger

Affiliations

Soon will be listed here.

Abstract

Objective: The cerebral microvasculature is rendered more vulnerable to thrombus formation following a brief (5.0 min) period of focal ischemia. This study examined the contribution of interleukin-6 (IL-6), a neuroprotective and prothrombotic cytokine produced by the brain, to transient ischemia-induced thrombosis in cerebral arterioles.

Approach & Results: The middle cerebral artery of C57BL/6J mice was occluded for 5 min, followed by 24h of reperfusion (MCAo/R). Intravital fluorescence microscopy was used to monitor thrombus development in cerebral arterioles induced by light/dye photoactivation. Thrombosis was quantified as the time of onset of platelet aggregation on the vessel wall and the time for complete blood flow cessation. MCAo/R in wild type (WT) mice yielded an acceleration of thrombus formation that was accompanied by increased IL-6 levels in plasma and in post-ischemic brain tissue. The exaggerated thrombosis response to MCAo/R was blunted in WT mice receiving an IL-6 receptor-blocking antibody and in IL-6 deficient (IL-6(-/-)) mice. Bone marrow chimeras, produced by transplanting IL-6(-/-) marrow into WT recipients, did not exhibit protection against MCAo/R-induced thrombosis.

Conclusions: The increased vulnerability of the cerebral vasculature to thrombus development after MCAo/R is mediated by IL-6, which is likely derived from brain cells rather than circulating blood cells. These findings suggest that anti-IL-6 therapy may reduce the likelihood of cerebral thrombus development after a transient ischemic attack.

Citing Articles

Baseline Serum Biomarkers of Inflammation and Subsequent Visit-to-Visit Blood Pressure Variability: A Post Hoc Analysis of MESA.

Wong K, Muddasani V, Peterson C, Sheibani N, Arkin C, Cheong I Am J Hypertens. 2022; 36(3):144-147.

PMID: 36315490 PMC: 11484580. DOI: 10.1093/ajh/hpac122.

Neuroprotective Effects of Theobromine in permanent bilateral common carotid artery occlusion rat model of cerebral hypoperfusion.

Bhat J, Kumar M Metab Brain Dis. 2022; 37(6):1787-1801.

PMID: 35587851 DOI: 10.1007/s11011-022-00995-6.

Liver vitronectin release into the bloodstream increases due to reduced vagal muscarinic signaling after cerebral stroke in female mice.

Keasey M, Lovins C, Jia C, Hagg T Physiol Rep. 2022; 10(9):e15301.

PMID: 35531929 PMC: 9082388. DOI: 10.14814/phy2.15301.

Identification of Host Factors Associated with the Development of Equine Herpesvirus Myeloencephalopathy by Transcriptomic Analysis of Peripheral Blood Mononuclear Cells from Horses.

Zarski L, Giessler K, Jacob S, Weber P, McCauley A, Lee Y Viruses. 2021; 13(3).

PMID: 33668216 PMC: 7995974. DOI: 10.3390/v13030356.

Ultrafast Hypothermia Selectively Mitigates the Early Humoral Response After Cardiac Arrest.

Boissady E, Kohlhauer M, Lidouren F, Hocini H, Lefebvre C, Chateau-Jouber S J Am Heart Assoc. 2020; 9(23):e017413.

PMID: 33198571 PMC: 7763769. DOI: 10.1161/JAHA.120.017413.

References

. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996; 348(9038):1329-39. DOI: 10.1016/s0140-6736(96)09457-3. View

van der Poll T, Levi M, Hack C, ten Cate H, van Deventer S, Eerenberg A . Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 1994; 179(4):1253-9. PMC: 2191443. DOI: 10.1084/jem.179.4.1253. View

Tang Y, Vital S, Russell J, Seifert H, Senchenkova E, Granger D . Transient ischemia elicits a sustained enhancement of thrombus development in the cerebral microvasculature: effects of anti-thrombotic therapy. Exp Neurol. 2014; 261:417-23. PMC: 4194261. DOI: 10.1016/j.expneurol.2014.07.004. View

Offner H, Vandenbark A, Hurn P . Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience. 2008; 158(3):1098-111. PMC: 2666964. DOI: 10.1016/j.neuroscience.2008.05.033. View

Shaafi S, Sharifipour E, Rahmanifar R, Hejazi S, Andalib S, Nikanfar M . Interleukin-6, a reliable prognostic factor for ischemic stroke. Iran J Neurol. 2014; 13(2):70-6. PMC: 4187333. View

Erta M, Quintana A, Hidalgo J . Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci. 2012; 8(9):1254-66. PMC: 3491449. DOI: 10.7150/ijbs.4679. View

Sacco R, Kasner S, Broderick J, Caplan L, Connors J, Culebras A . An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013; 44(7):2064-89. PMC: 11078537. DOI: 10.1161/STR.0b013e318296aeca. View

Kirino T . Ischemic tolerance. J Cereb Blood Flow Metab. 2002; 22(11):1283-96. DOI: 10.1097/01.WCB.0000040942.89393.88. View

Senchenkova E, Komoto S, Russell J, Almeida-Paula L, Yan L, Zhang S . Interleukin-6 mediates the platelet abnormalities and thrombogenesis associated with experimental colitis. Am J Pathol. 2013; 183(1):173-81. PMC: 3702741. DOI: 10.1016/j.ajpath.2013.03.014. View

10.

Woodroofe M, Sarna G, Wadhwa M, Hayes G, Loughlin A, Tinker A . Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol. 1991; 33(3):227-36. DOI: 10.1016/0165-5728(91)90110-s. View

11.

Yata K, Nishimura Y, Unekawa M, Tomita Y, Suzuki N, Tanaka T . In vivo imaging of the mouse neurovascular unit under chronic cerebral hypoperfusion. Stroke. 2014; 45(12):3698-703. DOI: 10.1161/STROKEAHA.114.005891. View

12.

Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A . Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab. 2005; 25(2):281-90. PMC: 2804085. DOI: 10.1038/sj.jcbfm.9600034. View

13.

Yan S, Russell J, Granger D . Platelet activation and platelet-leukocyte aggregation elicited in experimental colitis are mediated by interleukin-6. Inflamm Bowel Dis. 2014; 20(2):353-62. PMC: 3947085. DOI: 10.1097/01.MIB.0000440614.83703.84. View

14.

Spychalowicz A, Wilk G, Sliwa T, Ludew D, Guzik T . Novel therapeutic approaches in limiting oxidative stress and inflammation. Curr Pharm Biotechnol. 2012; 13(13):2456-66. View

15.

Gertz K, Kronenberg G, Kalin R, Baldinger T, Werner C, Balkaya M . Essential role of interleukin-6 in post-stroke angiogenesis. Brain. 2012; 135(Pt 6):1964-80. PMC: 3359750. DOI: 10.1093/brain/aws075. View

16.

Peng J, Friese P, George J, Dale G, BURSTEIN S . Alteration of platelet function in dogs mediated by interleukin-6. Blood. 1994; 83(2):398-403. View

17.

Chapman K, Dale V, Denes A, Bennett G, Rothwell N, Allan S . A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. J Cereb Blood Flow Metab. 2009; 29(11):1764-8. DOI: 10.1038/jcbfm.2009.113. View

18.

Field T, Nakajima M, Benavente O . Combination aspirin and clopidogrel for secondary prevention of ischemic stroke. Curr Treat Options Cardiovasc Med. 2013; 15(3):348-59. PMC: 3979285. DOI: 10.1007/s11936-013-0241-x. View

19.

Jung J, Kim G, Chan P . Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke. Stroke. 2011; 42(12):3574-9. PMC: 3395465. DOI: 10.1161/STROKEAHA.111.626648. View

20.

Diener H, Cunha L, Forbes C, Sivenius J, Smets P, LOWENTHAL A . European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143(1-2):1-13. DOI: 10.1016/s0022-510x(96)00308-5. View