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AIM2 levels and DNA-triggered inflammasome response are increased in peripheral leukocytes of patients with abdominal aortic aneurysm

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Abstract

Objective and design

Abdominal aortic aneurysm (AAA) is heavily infiltrated with leukocytes, expressing the DNA sensor absent in melanoma 2 (AIM2) and other inflammasome components.

Methods

Using multicolour flow cytometry, we here compared the expression of the inflammasome components AIM2, NLRP3, and ASC in different peripheral immune cells derived from AAA patients with those from non-AAA patients in a case–control study. In parallel, peripheral blood mononuclear cells (PBMC) of AAA patients and controls were stimulated in vitro with poly-dA:dT or lipopolysaccharide (LPS) to analyze inflammasome activation.

Results

AIM2 expression was significantly increased in peripheral granulocytes (P = 0.026), monocytes (P = 0.007), B lymphocytes (P < 0.0001), and T lymphocytes (P = 0.004) of AAA patients. Expression of other inflammasome components did not differ between the groups. Following in vitro stimulation with foreign DNA, PBMC derived from AAA patients released significantly more IL-1β (P = 0.022) into the supernatant than PBMC from control patients. In contrast, IL-1β release upon LPS stimulation did not differ between the PBMC groups.

Conclusion

The data indicate the increased activation of an AIM2 inflammasome in peripheral immune cells of AAA patients and point to a systemic AIM2-associated immune response to AAA.

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References

  1. Sampson UK, Norman PE, Fowkes FG, Aboyans V, Song Y, Harrell FE Jr, Forouzanfar MH, Naghavi M, Denenberg JO, McDermott MM, et al. Estimation of global and regional incidence and prevalence of abdominal aortic aneurysms 1990 to 2010. Glob Heart. 2014;9:159–70.

    Article  PubMed  Google Scholar 

  2. Brewster DC, Cronenwett JL, Hallett JW Jr, Johnston KW, Krupski WC, Matsumura JS, Joint Council of the American Association for Vascular S, Society for Vascular S. Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery. J Vasc Surg. 2003;37:1106–17.

    Article  PubMed  Google Scholar 

  3. Moll FL, Powell JT, Fraedrich G, Verzini F, Haulon S, Waltham M, van Herwaarden JA, Holt PJ, van Keulen JW, Rantner B, et al. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg. 2011;41(Suppl 1):1–58.

    Article  Google Scholar 

  4. Michel JB, Martin-Ventura JL, Egido J, Sakalihasan N, Treska V, Lindholt J, Allaire E, Thorsteinsdottir U, Cockerill G, Swedenborg J. Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc Res. 2011;90:18–27.

    Article  PubMed  CAS  Google Scholar 

  5. Nordon IM, Hinchliffe RJ, Loftus IM, Thompson MM. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol. 2011;8:92–102.

    Article  PubMed  Google Scholar 

  6. Dale MA, Ruhlman MK, Baxter BT. Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy. Arterioscler Thromb Vasc Biol. 2015;35(8):1746–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Brophy CM, Reilly JM, Smith GJ, Tilson MD. The role of inflammation in nonspecific abdominal aortic aneurysm disease. Ann Vasc Surg. 1991;5:229–33.

    Article  PubMed  CAS  Google Scholar 

  8. Newman KM, Jean-Claude J, Li H, Ramey WG, Tilson MD. Cytokines that activate proteolysis are increased in abdominal aortic aneurysms. Circulation. 1994;90:II224–227.

    PubMed  CAS  Google Scholar 

  9. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 1995;15:1145–51.

    Article  PubMed  CAS  Google Scholar 

  10. Johnston WF, Salmon M, Su G, Lu G, Stone ML, Zhao Y, Owens GK, Upchurch GR Jr, Ailawadi G. Genetic and pharmacologic disruption of interleukin-1beta signaling inhibits experimental aortic aneurysm formation. Arterioscler Thromb Vasc Biol. 2013;33:294–304.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Yoshimura K, Aoki H, Tsutsui H, Noda T, et al. Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm. Arterioscler Thromb Vasc Biol. 2015;35:127–36.

    Article  PubMed  CAS  Google Scholar 

  12. Wu D, Ren P, Zheng Y, Zhang L, Xu G, Xie W, Lloyd EE, Zhang S, Zhang Q, Curci JA, et al. NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome degrades contractile proteins: implications for aortic biomechanical dysfunction and aneurysm and dissection formation. Arterioscler Thromb Vasc Biol. 2017;37:694–706.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13:397–411.

    Article  PubMed  CAS  Google Scholar 

  14. Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. Eur J Immunol. 2016;46:269–80.

    Article  PubMed  CAS  Google Scholar 

  15. Hakimi M, Peters A, Becker A, Bockler D, Dihlmann S. Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis. J Vasc Surg. 2014;59:794–803 (e792).

    Article  PubMed  Google Scholar 

  16. Dihlmann S, Erhart P, Mehrabi A, Nickkholgh A, Lasitschka F, Bockler D, Hakimi M. Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms. Mol Med. 2014;20:230–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Wu X, Cakmak S, Wortmann M, Hakimi M, Zhang J, Bockler D, Dihlmann S. Sex- and disease-specific inflammasome signatures in circulating blood leukocytes of patients with abdominal aortic aneurysm. Mol Med. 2016; 22:508–518.

    Article  PubMed Central  CAS  Google Scholar 

  18. Wu X, Hakimi M, Wortmann M, Zhang J, Bockler D, Dihlmann S. Gene expression of inflammasome components in peripheral blood mononuclear cells (PBMC) of vascular patients increases with age. Immun Ageing. 2015;12:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Bengtsson H, Bergqvist D, Ekberg O, Janzon L. A population based screening of abdominal aortic aneurysms (AAA). Eur J Vasc Surg. 1991;5:53–7.

    Article  PubMed  CAS  Google Scholar 

  20. van Laarhoven CJ, Borstlap AC, van Berge Henegouwen DP, Palmen FM, Verpalen MC, Schoemaker MC. Chronic obstructive pulmonary disease and abdominal aortic aneurysms. Eur J Vasc Surg. 1993;7:386–90.

    Article  PubMed  Google Scholar 

  21. Bakele M, Joos M, Burdi S, Allgaier N, Poschel S, Fehrenbacher B, Schaller M, Marcos V, Kummerle-Deschner J, Rieber N, et al. Localization and functionality of the inflammasome in neutrophils. J Biol Chem. 2014;289:5320–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Svensson A, Patzi Churqui M, Schluter K, Lind L, Eriksson K. Maturation-dependent expression of AIM2 in human B-cells. PLoS One. 2017;12:e0183268.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yang CA, Huang ST, Chiang BL. Sex-dependent differential activation of NLRP3 and AIM2 inflammasomes in SLE macrophages. Rheumatology. 2015;54:324–31.

    Article  PubMed  CAS  Google Scholar 

  24. Algaba-Chueca F, de-Madaria E, Lozano-Ruiz B, Martinez-Cardona C, Quesada-Vazquez N, Bachiller V, Tarin F, Such J, Frances R, Zapater P, Gonzalez-Navajas JM. The expression and activation of the AIM2 inflammasome correlates with inflammation and disease severity in patients with acute pancreatitis. Pancreatology. 2017;17:364–71.

    Article  PubMed  CAS  Google Scholar 

  25. Choubey D, Panchanathan R. Absent in melanoma 2 proteins in SLE. Clin Immunol. 2017;176:42–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Lupfer CR, Rodriguez A, Kanneganti TD. Inflammasome activation by nucleic acids and nucleosomes in sterile inflammation… or is it sterile? FEBS J. 2017;284:2363–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Lozano-Ruiz B, Bachiller V, Garcia-Martinez I, Zapater P, Gomez-Hurtado I, Moratalla A, Gimenez P, Bellot P, Frances R, Such J, Gonzalez-Navajas JM. Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis. J Hepatol. 2015;62:64–71.

    Article  PubMed  CAS  Google Scholar 

  28. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Harris J, Lang T, Thomas JPW, Sukkar MB, Nabar NR, Kehrl JH. Autophagy and inflammasomes. Mol Immunol. 2017;86:10–5.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Houard X, Touat Z, Ollivier V, Louedec L, Philippe M, Sebbag U, Meilhac O, Rossignol P, Michel JB. Mediators of neutrophil recruitment in human abdominal aortic aneurysms. Cardiovasc Res. 2009;82:532–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank Anja Spieler (Department of Vascular and Endovascular Surgery of the University Hospital Heidelberg, Germany) for excellent technical assistance.

Funding

We acknowledge financial support by the Department of Vascular and Endovascular surgery of the University Hospital Heidelberg, Germany. This research was supported in part by a grant of the Deutsche Forschungsgemeinschaft (DFG; No. 323488362) to MW and SD.

Author information

Authors and Affiliations

  1. Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Markus Wortmann, Xianghui Xiao, Maani Hakimi, Dittmar Böckler & Susanne Dihlmann

  2. Institute for Immunology, Molecular Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany

    Guido Wabnitz & Yvonne Samstag

  3. Vascular Biobank Heidelberg (VBBH), Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Maani Hakimi

Authors
  1. Markus Wortmann
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  2. Xianghui Xiao
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  4. Yvonne Samstag
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  7. Susanne Dihlmann
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Corresponding author

Correspondence to Susanne Dihlmann.

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Conflict of interest

Xianghui Xiao has received financial support from the German Society of Vascular Surgery and Vascular Medicine for attending the annual meeting of the society in 2017. Maani Hakimi is CEO of CODE Medical Frankfurt GbR, Germany. Dittmar Böckler is consultant for Medtronic, W.L Gore & Ass. Endologix. The authors have no competing interests. MW, GW, YS, and SD have no conflict of interest for this publication.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Electronic supplementary material

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11_2019_1212_MOESM1_ESM.pdf

Gating strategy for phenotypic characterization of peripheral leukocytes that was applied for each individual AAA patient and age-matched subject without AAA. A. Live cells gated through the FSC-A versus SSC-A plot were selected and further characterized by plotting the SSC-A versus CD14-FITC, CD3-APC, or CD19-Cy5.5, respectively. Live CD14+ monocytes, CD3+ T cells and CD19+ B cells were then selected for analysis as shown in B. Granulocytes were defined as CD14- cells with a similar size a monocytes (SSC-A &#x003E; 120k). B. Histograms of the cells gated as shown in A. The fluorescent intensities of PE (representing NLRP3, AIM2 or ASC, horizontal axis) are plotted against the number of events detected (vertical axis, normalized to mode) in different leukocyte phenotypes. Dotted lines refer to the background, as it was determined by analysis of cells incubated with a PE-labeled secondary antibody only. The solid line (grey peak) refers to the fluorescent intensities of the PE-labeled secondary antibody that was used in combination with anti-NLRP3, anti-AIM2 or anti-ASC specific antibodies. The example shown refers to a control sample. SSC-A: side scatter (reflecting granularity of detected cells), area scaling. (PDF 174 KB)

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Wortmann, M., Xiao, X., Wabnitz, G. et al. AIM2 levels and DNA-triggered inflammasome response are increased in peripheral leukocytes of patients with abdominal aortic aneurysm. Inflamm. Res. 68, 337–345 (2019). https://doi.org/10.1007/s00011-019-01212-4

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  • DOI: https://doi.org/10.1007/s00011-019-01212-4

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