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Molecular Medicine

, Volume 20, Issue 1, pp 230–237 | Cite as

Increased Expression and Activation of Absent in Melanoma 2 Inflammasome Components in Lymphocytic Infiltrates of Abdominal Aortic Aneurysms

  • Susanne Dihlmann
  • Philipp Erhart
  • Arianeb Mehrabi
  • Arash Nickkholgh
  • Felix Lasitschka
  • Dittmar Böckler
  • Maani Hakimi
Research Article

Abstract

Chronic vascular inflammation is a key hallmark in the pathogenesis of abdominal aortic aneurysm (AAA). Recent investigations have suggested that the inflammasome, a cytosolic multiprotein complex that recognizes pathogen-associated molecular patterns, plays a role in atherosclerosis. However, its role in AAA inflammation has not yet been investigated. This pilot study analyzed inflammasome activation and its intramural localization in 24 biopsy samples from 11 patients with asymptomatic AAA versus 12 aortic samples from apparently healthy controls. Using a histological inflammation scale, we identified grade 2/3 inflammatory changes with lymphoid aggregates/tertiary lymphoid organs in 21 out of 24 AAA samples, whereas only 7 of the 12 control samples exhibited local grade 1 inflammatory changes. Strong expression levels of “apoptosis-associated speck-like protein with a caspase recruitment domain” (ASC), caspase-1, caspase-5 and “absent in melanoma 2” (AIM2) were detected by immunohis-tochemistry in both sporadic infiltrating lymphoid cells and lymphoid aggregates located in the outer media and adventitia of AAA samples. In contrast, inflammasome-positive cells were restricted to cholesterol plaque-associated areas and to single infiltrating cells in control aortas. Analysis of gene expression using real-time polymerase chain reaction (PCR) revealed significantly increased median mRNA levels of the inflammasome core components PYCARD (ASC), CASP1 (Caspase-1) and IL1B (IL-1β) in AAA tissue compared with normal aorta. Moreover, significantly increased median amounts of AIM2 protein and mature caspase-5 (p20) were found in samples associated with high rupture risk compared with paired low rupture risk samples of the same AAA patient. We conclude from our data that AAA-associated lymphoid cells are capable of inflammasome signaling, suggesting that inflammasome activation is involved in the chronic inflammatory process driving AAA progression.

Notes

Acknowledgements

We thank C Grond-Ginsbach (Department of Neurology, University Hospital Heidelberg, Germany) for useful discussions, A Spieler for excellent technical assistance in preparation of tissue samples and immunohistochemistry and C Kerber for technical assistance in real-time PCR. The tissue sampling by surgeons of the Department of Vascular and Endovascular Surgery and Transplant Surgery is greatly appreciated.

Supplementary material

10020_2014_2001230_MOESM1_ESM.pdf (490 kb)
Supplementary material, approximately 489 KB.

References

  1. 1.
    Michel JB, et al. (2011) Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc. Res. 90:18–27.CrossRefPubMedGoogle Scholar
  2. 2.
    Maiellaro K, Taylor WR. (2007) The role of the adventitia in vascular inflammation. Cardiovasc. Res. 75:640–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bobryshev YV, Lord RS. (2001) Vascular-associated lymphoid tissue (VALT) involvement in aortic aneurysm. Atherosclerosis. 154:15–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Ocana E, Bohorquez JC, Perez-Requena J, Brieva JA, Rodriguez C. (2003) Characterisation of T and B lymphocytes infiltrating abdominal aortic aneurysms. Atherosclerosis. 170:39–48.CrossRefPubMedGoogle Scholar
  5. 5.
    Wick G, et al. (1997) Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. FASEB J. 11:1199–207.CrossRefPubMedGoogle Scholar
  6. 6.
    Yin Y, et al. (2009) Inflammasomes are differentially expressed in cardiovascular and other tissues. Int. J. Immunopathol. Pharmacol. 22:311–22.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Duewell P, et al. (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 464:1357–61.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Strowig T, Henao-Mejia J, Elinav E, Flavell R. (2012) Inflammasomes in health and disease. Nature. 481:278–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Lamkanfi M, Dixit VM. (2012) Inflammasomes and their roles in health and disease. Annu. Rev. Cell. Dev. Biol. 28:137–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Jiang Y, et al. (2012) Oxidized low-density lipoprotein induces secretion of interleukin-1β by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem. Biophys. Res. Commun. 425:121–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Yajima N, et al. (2008) Critical role of bone marrow apoptosis-associated speck-like protein, an inflammasome adaptor molecule, in neointimal formation after vascular injury in mice. Circulation. 117:3079–87.CrossRefPubMedGoogle Scholar
  12. 12.
    Usui F, et al. (2012) Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice. Biochem. Biophys. Res. Commun. 425:162–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Hakimi M, Peters A, Becker A, Böckler D, Dihlmann S. (2013) Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis. J. Vasc. Surg. 794–803.e2.Google Scholar
  14. 14.
    Newman KM, Jean-Claude J, Li H, Ramey WG, Tilson MD. (1994) Cytokines that activate proteolysis are increased in abdominal aortic aneurysms. Circulation. 90: II224–7.PubMedGoogle Scholar
  15. 15.
    Keen RR, et al. (1994) Interleukin-1 beta induces differential gene expression in aortic smooth muscle cells. J. Vasc. Surg. 20:774–84; discussion 784–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Gasser TC, Auer M, Labruto F, Swedenborg J, Roy J. (2010) Biomechanical rupture risk assessment of abdominal aortic aneurysms: model complexity versus predictability of finite element simulations. Eur. J. Vasc. Endovasc. Surg. 40:176–85.CrossRefPubMedGoogle Scholar
  17. 17.
    Martufi G, Christian Gasser T. (2013) Review: the role of biomechanical modeling in the rupture risk assessment for abdominal aortic aneurysms. J. Biomech. Eng. 135:021010.CrossRefPubMedGoogle Scholar
  18. 18.
    Hyhlik-Dürr A, et al. (2011) Reproducibility of deriving parameters of AAA rupture risk from patient-specific 3D finite element models. J. Endovasc. Ther. 18:289–98.CrossRefPubMedGoogle Scholar
  19. 19.
    Rijbroek A, Moll FL, von Dijk HA, Meijer R, Jansen JW. (1994) Inflammation of the abdominal aortic aneurysm wall. Eur. J. Vasc. Surg. 8:41–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Lee J, Li L, Gretz N, Gebert J, Dihlmann S. (2012) Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers. Oncogene. 31:1242–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Latz E, Xiao TS, Stutz A. (2013) Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13:397–411.CrossRefPubMedGoogle Scholar
  22. 22.
    Sanos SL, Diefenbach A. (2013) Innate lymphoid cells: from border protection to the initiation of inflammatory diseases. Immunol. Cell. Biol. 91:215–24.CrossRefPubMedGoogle Scholar
  23. 23.
    Gerlic M, et al. (2013) Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation. Proc. Natl. Acad. Sci U. S. A. 110:7808–13.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Perez-Lopez A, Rosales-Reyes R, Alpuche-Aranda CM, Ortiz-Navarrete V. (2013) Salmonella down-regulates Nod-like receptor family CARD domain containing protein 4 expression to promote its survival in B cells by preventing inflammasome activation and cell death. J. Immunol. 190:1201–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Singh VV, et al. (2013) Kaposi’s sarcoma-associated herpesvirus latency in endothelial and B cells activates gamma interferon-inducible protein 16-mediated inflammasomes. J. Virol. 87:4417–4431.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Martinon F, Tschopp J. (2007) Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14:10–22.CrossRefPubMedGoogle Scholar
  27. 27.
    Salskov-Iversen ML, Johansen C, Kragballe K, Iversen L. (2011) Caspase-5 expression is upregu-lated in lesional psoriatic skin. J. Invest. Dermatol. 131:670–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Bian ZM, et al. (2011) Expression and functional roles of caspase-5 in inflammatory responses of human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 52:8646–56.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Powell JT, et al. (2011) Rupture rates of small abdominal aortic aneurysms: a systematic review of the literature. Eur. J. Vasc. Endovasc. Surg. 41:2–10.CrossRefPubMedGoogle Scholar
  30. 30.
    Darling RC, Messina CR, Brewster DC, Ottinger LW. (1977) Autopsy study of unoperated abdominal aortic aneurysms. The case for early resection. Circulation 56(3 Suppl):II161–4.PubMedGoogle Scholar
  31. 31.
    Courtois A, et al. (2013) 18F-FDG uptake assessed by PET/CT in abdominal aortic aneurysms is associated with cellular and molecular alterations prefacing wall deterioration and rupture. J. Nucl. Med. 54:1740–7.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Susanne Dihlmann
    • 1
  • Philipp Erhart
    • 1
  • Arianeb Mehrabi
    • 2
  • Arash Nickkholgh
    • 2
  • Felix Lasitschka
    • 3
  • Dittmar Böckler
    • 1
  • Maani Hakimi
    • 1
  1. 1.Department of Vascular and Endovascular SurgeryUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Department of General, Visceral and Transplantation SurgeryUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany

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