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Open Access 01-12-2016 | Research

Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells

Authors: David M. Sawyer, Lauren A. Pace, Crissey L. Pascale, Alexander C. Kutchin, Brannan E. O’Neill, Robert M. Starke, Aaron S. Dumont

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Intracranial aneurysms (IA) are increasingly recognized as a disease driven by chronic inflammation. Recent research has identified key mediators and processes underlying IA pathogenesis, but mechanistic understanding remains incomplete. Lymphocytic infiltrates have been demonstrated in patient IA tissue specimens and have also been shown to play an important role in abdominal aortic aneurysms (AAA) and related diseases such as atherosclerosis. However, no study has systematically examined the contribution of lymphocytes in a model of IA.

Methods

Lymphocyte-deficient (Rag1) and wild-type (WT; C57BL/6 strain) mice were subjected to a robust IA induction protocol. Rates of IA formation and rupture were measured, and cerebral artery tissue was collected and utilized for histology and gene expression analysis.

Results

At 2 weeks, the Rag1 group had significantly fewer IA formations and ruptures than the WT group. Histological analysis of unruptured IA tissue showed robust B and T lymphocyte infiltration in the WT group, while there were no differences in macrophage infiltration, IA diameter, and wall thickness. Significant differences in interleukin-6 (IL-6), matrix metalloproteinases 2 (MMP2) and 9 (MMP9), and smooth muscle myosin heavy chain (MHC) were observed between the groups.

Conclusions

Lymphocytes are key contributors to IA pathogenesis and provide a novel target for the prevention of IA progression and rupture in patients.

Rinkel GJ. Natural history, epidemiology and screening of unruptured intracranial aneurysms. J Neuroradiol. 2008;35:99–103.CrossRefPubMed

Komotar RJ, Zacharia BE, Mocco J, Connolly Jr ES. Controversies in the surgical treatment of ruptured intracranial aneurysms: the First Annual J. Lawrence Pool Memorial Research Symposium—controversies in the management of cerebral aneurysms. Neurosurgery. 2008;62:396–407. discussion 405-397.CrossRefPubMed

Brown Jr RD, Huston J, Hornung R, Foroud T, Kallmes DF, Kleindorfer D, Meissner I, Woo D, Sauerbeck L, Broderick J. Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection. J Neurosurg. 2008;108:1132–8.CrossRefPubMedPubMedCentral

Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med. 2006;355:928–39.CrossRefPubMed

van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369:306–18.CrossRefPubMed

Kassell NF, Torner JC. The International Cooperative Study on Timing of Aneurysm Surgery—an update. Stroke. 1984;15:566–70.CrossRefPubMed

Schievink WI. Intracranial aneurysms. N Engl J Med. 1997;336:28–40.CrossRefPubMed

Ronkainen A, Miettinen H, Karkola K, Papinaho S, Vanninen R, Puranen M, Hernesniemi J. Risk of harboring an unruptured intracranial aneurysm. Stroke. 1998;29:359–62.CrossRefPubMed

Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997;28:491–9.CrossRefPubMed

10.

Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology. 1998;50:1413–8.CrossRefPubMed

11.

Krishnamurthi RV, Moran AE, Forouzanfar MH, Bennett DA, Mensah GA, Lawes CM, Barker-Collo S, Connor M, Roth GA, Sacco R, et al. The global burden of hemorrhagic stroke: a summary of findings from the GBD 2010 study. Glob Heart. 2014;9:101–6.CrossRefPubMed

12.

de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry. 2007;78:1365–72.CrossRefPubMedPubMedCentral

13.

Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Koch WJ, Dumont AS. Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab. 2012;32:1659–76.CrossRefPubMedPubMedCentral

14.

Sawyer DM, Amenta PS, Medel R, Dumont AS. Inflammatory mediators in vascular disease: identifying promising targets for intracranial aneurysm research. Mediators Inflamm. 2015;2015:896283.CrossRefPubMedPubMedCentral

15.

Starke RM, Chalouhi N, Ding D, Raper DM, McKisic MS, Owens GK, Hasan DM, Medel R, Dumont AS. Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res. 2014;5:338–46.CrossRefPubMed

16.

Tulamo R, Frosen J, Hernesniemi J, Niemela M. Inflammatory changes in the aneurysm wall: a review. J Neurointerv Surg. 2010;2:120–30.CrossRefPubMed

17.

Hasan D, Chalouhi N, Jabbour P, Hashimoto T. Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J Neuroinflammation. 2012;9:222.CrossRefPubMedPubMedCentral

18.

Henderson EL, Geng YJ, Sukhova GK, Whittemore AD, Knox J, Libby P. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation. 1999;99:96–104.CrossRefPubMed

19.

Chyatte D, Bruno G, Desai S, Todor DR. Inflammation and intracranial aneurysms. Neurosurgery. 1999;45:1137–46. discussion 1146-1137.CrossRefPubMed

20.

Kosierkiewicz TA, Factor SM, Dickson DW. Immunocytochemical studies of atherosclerotic lesions of cerebral berry aneurysms. J Neuropathol Exp Neurol. 1994;53:399–406.CrossRefPubMed

21.

Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke. 2004;35:2287–93.CrossRefPubMed

22.

Tse K, Tse H, Sidney J, Sette A, Ley K. T cells in atherosclerosis. Int Immunol. 2013;25:615–22.CrossRefPubMedPubMedCentral

23.

Lintermans LL, Stegeman CA, Heeringa P, Abdulahad WH. T cells in vascular inflammatory diseases. Front Immunol. 2014;5:504.CrossRefPubMedPubMedCentral

24.

Ammirati E, Moroni F, Magnoni M, Camici PG. The role of T and B cells in human atherosclerosis and atherothrombosis. Clin Exp Immunol. 2015;179:173–87.CrossRefPubMedPubMedCentral

25.

Nuki Y, Tsou TL, Kurihara C, Kanematsu M, Kanematsu Y, Hashimoto T. Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension. 2009;54:1337–44.CrossRefPubMedPubMedCentral

26.

Starke RM, Chalouhi N, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Wada K, Shimada K, Hasan DM, Greig NH, et al. Critical role of TNF-alpha in cerebral aneurysm formation and progression to rupture. J Neuroinflammation. 2014;11:77.CrossRefPubMedPubMedCentral

27.

Burgess A, Vigneron S, Brioudes E, Labbe JC, Lorca T, Castro A. Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance. Proc Natl Acad Sci U S A. 2010;107:12564–9.CrossRefPubMedPubMedCentral

28.

Keedy A. An overview of intracranial aneurysms. Mcgill J Med. 2006;9:141–6.PubMedPubMedCentral

29.

Ocana E, Bohorquez JC, Perez-Requena J, Brieva JA, Rodriguez C. Characterisation of T and B lymphocytes infiltrating abdominal aortic aneurysms. Atherosclerosis. 2003;170:39–48.CrossRefPubMed

30.

Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 1813;2011:878–88.

31.

Shimada K, Furukawa H, Wada K, Korai M, Wei Y, Tada Y, Kuwabara A, Shikata F, Kitazato KT, Nagahiro S, et al. Protective role of peroxisome proliferator-activated receptor-gamma in the development of intracranial aneurysm rupture. Stroke. 2015;46:1664–72.CrossRefPubMedPubMedCentral

32.

Kao HW, Lee KW, Kuo CL, Huang CS, Tseng WM, Liu CS, Lin CP. Interleukin-6 as a prognostic biomarker in ruptured intracranial aneurysms. PLoS One. 2015;10:e0132115.CrossRefPubMedPubMedCentral

33.

McColgan P, Thant KZ, Sharma P. The genetics of sporadic ruptured and unruptured intracranial aneurysms: a genetic meta-analysis of 8 genes and 13 polymorphisms in approximately 20,000 individuals. J Neurosurg. 2010;112:714–21.CrossRefPubMed

34.

Sathyan S, Koshy LV, Srinivas L, Easwer HV, Premkumar S, Nair S, Bhattacharya RN, Alapatt JP, Banerjee M. Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors. J Neuroinflammation. 2015;12:135.CrossRefPubMedPubMedCentral

35.

Pena Silva RA, Kung DK, Mitchell IJ, Alenina N, Bader M, Santos RA, Faraci FM, Heistad DD, Hasan DM. Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice. Hypertension. 2014;64:362–8.CrossRefPubMedPubMedCentral

36.

Wakisaka Y, Chu Y, Miller JD, Rosenberg GA, Heistad DD. Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. J Cereb Blood Flow Metab. 2010;30:56–69.CrossRefPubMed

37.

Caird J, Napoli C, Taggart C, Farrell M, Bouchier-Hayes D. Matrix metalloproteinases 2 and 9 in human atherosclerotic and non-atherosclerotic cerebral aneurysms. Eur J Neurol. 2006;13:1098–105.CrossRefPubMed

38.

Bruno G, Todor R, Lewis I, Chyatte D. Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg. 1998;89:431–40.CrossRefPubMed

39.

Jin D, Sheng J, Yang X, Gao B. Matrix metalloproteinases and tissue inhibitors of metalloproteinases expression in human cerebral ruptured and unruptured aneurysm. Surg Neurol. 2007;68 Suppl 2:S11–16. discussion S16.CrossRefPubMed

40.

Li L, Miano JM, Cserjesi P, Olson EN. SM22 alpha, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis. Circ Res. 1996;78:188–95.CrossRefPubMed

41.

Caplice NM, Bunch TJ, Stalboerger PG, Wang S, Simper D, Miller DV, Russell SJ, Litzow MR, Edwards WD. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci U S A. 2003;100:4754–9.CrossRefPubMedPubMedCentral

42.

Miano JM, Cserjesi P, Ligon KL, Periasamy M, Olson EN. Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis. Circ Res. 1994;75:803–12.CrossRefPubMed

43.

Sibon I, Mercier N, Darret D, Lacolley P, Lamaziere JM. Association between semicarbazide-sensitive amine oxidase, a regulator of the glucose transporter, and elastic lamellae thinning during experimental cerebral aneurysm development: laboratory investigation. J Neurosurg. 2008;108:558–66.CrossRefPubMed

44.

Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449–60.CrossRefPubMedPubMedCentral

Title: Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells
Authors: David M. Sawyer
Lauren A. Pace
Crissey L. Pascale
Alexander C. Kutchin
Brannan E. O’Neill
Robert M. Starke
Aaron S. Dumont
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0654-z

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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