Advertisement

Deletion of interleukin-18 attenuates abdominal aortic aneurysm formation

      Highlights

      • IL-18 deletion attenuated abdominal aortic aneurysm (AAA) formation.
      • IL-18 induced enhanced expression of osteopontin in vascular smooth muscle cells.
      • IL-18 contributes to inflammation and matrix metalloproteinase activation in AAA.

      Abstract

      Background and aims

      Abdominal aortic aneurysm (AAA) is a common disease; however, its exact pathogenesis remains unknown, and no specific medical therapies are available. Interleukin (IL)-18 plays a crucial role in atherosclerotic plaque destabilization and is a strong predictor of cardiovascular death. Here, we investigated the role of IL-18 in AAA pathogenesis using an experimental mouse model.

      Methods and results

      After infusion of angiotensin II (Ang II) for 4 weeks and β-aminopropionitrile (BAPN) for 2 weeks, 58% of C57/6J wild-type (WT) mice developed AAA associated with enhanced expression of IL-18; however, disease incidence was significantly lower in IL-18−/− mice than in WT mice (p < 0.01), although no significant difference was found in systolic blood pressure between WT mice and IL-18−/− mice in this model. Additionally, IL-18 deletion significantly attenuated Ang II/BAPN-induced macrophage infiltration, macrophage polarization into inflammatory M1 phenotype, and matrix metalloproteinase (MMP) activation in abdominal aortas, which is associated with reduced expression of osteopontin (OPN).

      Conclusions

      These findings indicate that IL-18 plays an important role in the development of AAA by enhancing OPN expression, macrophage recruitment, and MMP activation. Moreover, IL-18 represents a previously unrecognized therapeutic target for the prevention of AAA formation.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ashton H.A.
        • Buxton M.J.
        • Day N.E.
        • et al.
        The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial.
        Lancet (London, Engl.). 2002; 360: 1531-1539
        • Lederle F.A.
        Ultrasonographic screening for abdominal aortic aneurysms.
        Ann. Intern. Med. 2003; 139: 516-522
        • Ashton H.A.
        • Gao L.
        • Kim L.G.
        • et al.
        Fifteen-year follow-up of a randomized clinical trial of ultrasonographic screening for abdominal aortic aneurysms.
        Br. J. Surg. 2007; 94: 696-701
        • Hoornweg L.L.
        • Storm-Versloot M.N.
        • Ubbink D.T.
        • et al.
        Meta analysis on mortality of ruptured abdominal aortic aneurysms.
        Eur. J. Vasc. Endovasc. Surg. : Off. J. Eur. Soc. Vasc. Surg. 2008; 35: 558-570
        • Davis F.M.
        • Rateri D.L.
        • Daugherty A.
        Abdominal aortic aneurysm: novel mechanisms and therapies.
        Curr. Opin. Cardiol. 2015; 30: 566-573
        • Golledge J.
        • Norman P.E.
        • Murphy M.P.
        • et al.
        Challenges and opportunities in limiting abdominal aortic aneurysm growth.
        J. Vasc. Surg. 2017; 65: 225-233
        • Raffort J.
        • Lareyre F.
        • Clement M.
        • et al.
        Monocytes and macrophages in abdominal aortic aneurysm.
        Nat. Rev. Cardiol. 2017; 14: 457-471
        • Eliason J.L.
        • Hannawa K.K.
        • Ailawadi G.
        • et al.
        Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation.
        Circulation. 2005; 112: 232-240
        • Swedenborg J.
        • Mayranpaa M.I.
        • Kovanen P.T.
        Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms.
        Arterioscler. Thromb. Vasc. Biol. 2011; 31: 734-740
        • Yan H.
        • Zhou H.F.
        • Akk A.
        • et al.
        Neutrophil proteases promote experimental abdominal aortic aneurysm via extracellular trap release and plasmacytoid dendritic cell activation.
        Arterioscler. Thromb. Vasc. Biol. 2016; 36: 1660-1669
        • Quintana R.A.
        • Taylor W.R.
        Cellular mechanisms of aortic aneurysm formation.
        Circ. Res. 2019; 124: 607-618
        • Daugherty A.
        • Powell J.T.
        Recent highlights of ATVB: aneurysms.
        Arterioscler. Thromb. Vasc. Biol. 2014; 34: 691-694
        • Hajishengallis G.
        • Chavakis T.
        Endogenous modulators of inflammatory cell recruitment.
        Trends Immunol. 2013; 34: 1-6
        • Cho H.J.
        • Cho H.J.
        • Kim H.S.
        Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification.
        Curr. Atheroscler. Rep. 2009; 11: 206-213
        • Wang Y.
        • Tang C.
        • Qin Y.
        Cathepsins: a new culprit behind abdominal aortic aneurysm.
        Regen. Med. Res. 2013; 1: 5
        • Bendeck M.P.
        • Irvin C.
        • Reidy M.
        • et al.
        Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1467-1472
        • Yu Q.
        • Vazquez R.
        • Khojeini E.V.
        • et al.
        IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice.
        Am. J. Physiol. Heart Circ. Physiol. 2009; 297: H76-H85
        • Bruemmer D.
        • Collins A.R.
        • Noh G.
        • et al.
        Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice.
        J. Clin. Invest. 2003; 112: 1318-1331
        • Sedimbi S.K.
        • Hagglof T.
        • Karlsson M.C.
        IL-18 in inflammatory and autoimmune disease.
        Cell. Mol. Life Sci. : CM. 2013; 70: 4795-4808
        • Ahmad R.
        • Al-Mass A.
        • Al-Ghawas D.
        • et al.
        Interaction of osteopontin with IL-18 in obese individuals: implications for insulin resistance.
        PLoS One. 2013; 8e63944
        • Mallat Z.
        • Corbaz A.
        • Scoazec A.
        • et al.
        Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability.
        Circ. Res. 2001; 89: E41-E45
        • Kanematsu Y.
        • Kanematsu M.
        • Kurihara C.
        • et al.
        Pharmacologically induced thoracic and abdominal aortic aneurysms in mice.
        Hypertension. 2010; 55: 1267-1274
        • Kawai T.
        • Takayanagi T.
        • Forrester S.J.
        • et al.
        Vascular ADAM17 (a disintegrin and metalloproteinase domain 17) is required for angiotensin II/beta-Aminopropionitrile-Induced abdominal aortic aneurysm.
        Hypertension. 2017; 70: 959-963
        • Johnston W.F.
        • Salmon M.
        • Su G.
        • et al.
        Genetic and pharmacologic disruption of interleukin-1beta signaling inhibits experimental aortic aneurysm formation.
        Arterioscler. Thromb. Vasc. Biol. 2013; 33: 294-304
        • Sharma A.K.
        • Lu G.
        • Jester A.
        • et al.
        Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment.
        Circulation. 2012; 126: S38-S45
        • Martinez-Lopez D.
        • Cedo L.
        • Metso J.
        • et al.
        Impaired HDL (High-Density lipoprotein)-mediated macrophage cholesterol efflux in patients with abdominal aortic aneurysm-brief report.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 2750-2754
        • Obama T.
        • Tsuji T.
        • Kobayashi T.
        • et al.
        Epidermal growth factor receptor inhibitor protects against abdominal aortic aneurysm in a mouse model.
        Clin. Sci. 2015; 128 (London, England : 1979): 559-565
        • Guzik T.J.
        • Touyz R.M.
        Oxidative stress, inflammation, and vascular aging in hypertension.
        Hypertension. 2017; 70: 660-667
        • Swanson K.V.
        • Deng M.
        • Ting J.P.
        The NLRP3 inflammasome: molecular activation and regulation to therapeutics.
        Nat. Rev. Immunol. 2019; 19: 477-489
        • Tan H.W.
        • Liu X.
        • Bi X.P.
        • et al.
        IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome.
        Atherosclerosis. 2010; 208: 350-357
        • de Nooijer R.
        • von der Thusen J.H.
        • Verkleij C.J.
        • et al.
        Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2004; 24: 2313-2319
        • Bhat O.M.
        • Kumar P.U.
        • Giridharan N.V.
        • et al.
        Interleukin-18-induced atherosclerosis involves CD36 and NF-kappaB crosstalk in Apo E-/- mice.
        J. Cardiol. 2015; 66: 28-35
        • Chandrasekar B.
        • Mummidi S.
        • Mahimainathan L.
        • et al.
        Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB- and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin.
        J. Biol. Chem. 2006; 281: 15099-15109
        • Reddy V.S.
        • Valente A.J.
        • Delafontaine P.
        • et al.
        Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation.
        J. Cell. Physiol. 2011; 226: 3303-3315
        • Sahar S.
        • Dwarakanath R.S.
        • Reddy M.A.
        • et al.
        Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells: a novel cross-talk in the pathogenesis of atherosclerosis.
        Circ. Res. 2005; 96: 1064-1071
        • Yoo J.K.
        • Kwon H.
        • Khil L.Y.
        • et al.
        IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways.
        J. Immunol. 2005; 175 (Baltimore, Md. : 1950): 8280-8286
        • Goodison S.
        • Urquidi V.
        • Tarin D.
        CD44 cell adhesion molecules.
        Mol. Pathol. 1999; 52: 189-196
        • Berrier A.L.
        • Yamada K.M.
        Cell-matrix adhesion.
        J. Cell. Physiol. 2007; 213: 565-573
        • Lund S.A.
        • Wilson C.L.
        • Raines E.W.
        • et al.
        Osteopontin mediates macrophage chemotaxis via alpha4 and alpha9 integrins and survival via the alpha4 integrin.
        J. Cell. Biochem. 2013; 114: 1194-1202
        • Mallat Z.
        • Corbaz A.
        • Scoazec A.
        • et al.
        Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability.
        Circulation. 2001; 104: 1598-1603
        • Whitman S.C.
        • Ravisankar P.
        • Daugherty A.
        Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma.
        Circ. Res. 2002; 90: E34-E38
        • Gupta S.
        • Pablo A.M.
        • Jiang X.
        • et al.
        IFN-gamma potentiates atherosclerosis in ApoE knock-out mice.
        J. Clin. Invest. 1997; 99: 2752-2761
        • Zhou H.F.
        • Yan H.
        • Cannon J.L.
        • et al.
        CD43-mediated IFN-gamma production by CD8+ T cells promotes abdominal aortic aneurysm in mice.
        J. Immunol. 2013; 190 (Baltimore, Md. : 1950): 5078-5085
        • Xiong W.
        • Zhao Y.
        • Prall A.
        • et al.
        Key roles of CD4+ T cells and IFN-gamma in the development of abdominal aortic aneurysms in a murine model.
        J. Immunol. 2004; 172 (Baltimore, Md. : 1950): 2607-2612
        • Shimizu K.
        • Shichiri M.
        • Libby P.
        • et al.
        Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas.
        J. Clin. Invest. 2004; 114: 300-308
        • King V.L.
        • Lin A.Y.
        • Kristo F.
        • et al.
        Interferon-gamma and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture.
        Circulation. 2009; 119: 426-435
        • Guo D.C.
        • Papke C.L.
        • He R.
        • et al.
        Pathogenesis of thoracic and abdominal aortic aneurysms.
        Ann. N. Y. Acad. Sci. 2006; 1085: 339-352