doi: 10.1161/01.RES.0000251794.69345.0c
© 2006 American Heart Association, Inc.
Editorials |
A Novel Approach to the Suppression of Atherosclerosis by Fc
Receptor Blockade
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
Correspondence to Chiharu Kishimoto, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kkishi{at}kuhp.kyoto-u.ac
See related article, pages 1188–1196
Key Words: Fc receptors • atherosclerosis • myocarditis • immunoglobulin
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Introduction |
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A therosclerosis is associated with immune activation and with systemic immune responses and signs of inflammation.1–3 Atherosclerotic plaques contain a large number of immune cells, particularly macrophages and T cells.4,5 Histopathological and clinical investigations point to immune activation of plaques as a cause of plaque rupture and acute coronary syndromes. Seroepidemiological studies suggest links between atherosclerosis and microbial infections.6,7 Animal studies have identified specific immune cells that play a role in atherogenesis. For example, congenital deficiency of macrophages, lymphocytes, and the Th1 effector pathway, generated by cross-breeding apolipoprotein (apo) E knockout (KO) mice with op/op mutant mice,8 recombinase acting gene-1 KO mice,9 and interferon-
receptor KO mice,10 respectively, have resulted in the reduction of aherosclerotic lesions. Furthermore, the blockade of c-fms, a receptor for macrophage colony stimulating factor, also caused marked suppression of atherogenesis in apo E-deficient mice, where macrophage differentiation was impaired. These and other studies suggest that immunomodulation may be used to treat or prevent atherosclerosis. Therapy with immunoglobulin has been used in the treatment of immune-mediated disorders for more than 25 years.11–13 The mode of action of immunoglobulin is still unclear and may involve both Fc and V region-dependent mechanisms: blockade of Fc receptors on macrophages and effector cells, antiinflammatory effects by attenuation of complement-mediated damage, regulation of the production of cytokines, or inhibition of lymphocyte proliferation. Several of these mechanisms might be beneficial in atherosclerosis.14 Indeed, we have found that immunoglobulin therapy markedly suppressed atherosclerosis because of Fc receptor-mediated immunomodulatory actions in apoE-deficient mice.15
In the present issue of Circulation Research, Hernández-Vargas et al report that Fc receptor deficiency protects against the development of atherosclerosis in apo E KO mice.16 Using double knock out (DKO) mice by crossing apo E KO mice with IgG Fc receptors (FcRs) deficient mice, they demonstrated that DKO mice exhibited a reduction in the atherosclerotic lesion size compared with apoE KO, control mice without alterations in serum lipid profiles. FcR deficiency in DKO mice significantly diminished the macrophage and T cell count, the expression of monocyte chemoatlractant protein-1, regulated on activated normal T-cell expressed and secreted (RANTES), and adhesion molecule-1 in the lesions. In addition, cultured vascular smooth muscle cells from both FcR deficient and DKO mice failed to respond to immune complexes, shown by impaired chemokine expression and NF-
B activation. Furthermore, DKO mice exhibited lack expression of FcRI and FcRIIIA (both activating receptors), while FcRIIB (inhibiting receptor) was potentiated. The authors concluded that FcR deficiency limits development and progression of atherosclerosis, and pointed out the critical role of FcRs in atherogenesis.
Fc receptors act as trigger molecules for inflammation, allergic, endocytotic, and inhibitory activities of immune effector cells.17 Recently, specific classes or FcRs have been well characterized.18 Two general classes of FcRs are known, the activating and the inhibitory receptors, which transmit their signals via immunoreceptor typosine-based activation (ITAM) or inhibitory motifs (ITIM). In activating receptors, the ITAM motif can be intrinsic to the receptor, as in FcRIIA (a receptor not found in the mouse), and in FcRI, FcRIIIA, and FcRIV (receptors conserved between mouse and human). The inhibitory receptor (FcRIIB) contains the ITIM sequence, and binds IgG and immune complexes with low affinity. Recently, it has been postulated that FcR activation is involved in a wide range of inflammatory and immune diseases.18–21 Accordingly, a novel therapeutic target in atherosclerosis is the FcR.
In previous studies, FcRIIB mediated not only an inhibitory effect on experimental autoimmune myocarditis in rats13 but also an antiatherosclerotic effect in apo E deficient mice,15 using the entire immunoglobulin molecule. Specifically, an intact immunoglobulin, but not F(ab')2 fragments of immunoglobulin, inhibited myocarditis or atherosclerosis through the Fc portion. Gill et al22 demonstrated the targeting effect of immunoglobulin on adhesion molecules using ischemia/reperfusion model in cats, suggesting the downregulation of adhesion molecules via Fc receptors. Recently, it has been shown that Fc receptors play a pivotal role in experimental neointimal vascular hyperplasia via ITIM.23 Furthermore, Mineo et al demonstrated FcRIIB-mediated C-reactive protein (CRP) inhibition of endothelial nitric oxide (NO) synthase.24 They found that in control mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance, and that, in contrast, CRP enhances a cetylcholine responses in FcRIIB KO mice.24
It is known that FcRIIB is expressed in human endothelial cells and in mouse endothelium,24 and that CRP levels are strongly correlated with increased risk for myocardial and vascular inflammatory diseases.25,26 Based on the current study and also on previously published data, FcIIB blockade may be a novel therapy for inflammatory cardiovascular diseases.
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This work was supported in part by grants from Japanese Ministry of Education, Science, and Culture (18590772) and Chiyoda Kenko Organization.
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Disclosures |
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None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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1. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol. 2001; 21: 1876–1890.
2. Libby P, Hansson GK. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991; 64: 5–15.[Medline] [Order article via Infotrieve]
3. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
4. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Atherosclerosis. 1986; 6: 131–138.[Medline] [Order article via Infotrieve]
5. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995; 92: 3893–3897.
6. Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Rippin G, Victor A, Hafner G, Schlumberger W, Meyer J. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation. 2002; 105: 15–21.
7. Memon RA, Staprans I, Noor M, Holleran WM, Uchida Y, Moser AH, Feingold KR, Grunfeld C. Infection and inflammation induce LDL oxidation in vivo. Arterioscler Thromb Vasc Biol. 2000; 20: 1536–1542.
8. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995; 92: 8264–8268.
9. Dansky HM, Charlton SA, Harper MM, Smith JD. T and B lymphocytes play a minor role in atherosclerosis plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1997; 94: 4642–4646.
10. Gupta S, Pablo AM, Jiang X, Wang N, Tall AR, Schindler C. IFN- potentiates atherosclerosis in Apo E knock-out mice. J Clin Invest. 1997; 99: 2752–2761.[Medline]
[Order article via Infotrieve]
11. Godeau B, Chevret S, Varet B, Lefrere F, Zini JM, Bassompierre F, Cheze S, Legouffe E, Hulin C, Grange MJ, Fain O, Bierling P. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomized, multicentre trial. Lancet. 2002; 359: 23–29.[CrossRef][Medline] [Order article via Infotrieve]
12. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001; 345: 747–755.
13. Shioji K, Kishimoto C, Sasayama S. Fc receptor-mediated inhibitory effect of immunoglobulin therapy on autoimmune giant cell myocarditis: concomitant suppression of the expression of dendritic cells. Circ Res. 2001; 89: 540–546.
14. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest. 1998; 102: 910–918.[Medline] [Order article via Infotrieve]
15. Yuan Z, Kishimoto C, Sano H, Shioji K, Xu Y, Yokode M. Immunoglobulin treatment suppresses atherosclerosis in apolipoprotein E-deficient mice via the Fc portion. Am J Physiol Heart Circ Physiol. 2003; 285: H899–H906.
16. Hernandez-Vargas P, Ortiz-Munoz G, Lopez-Franco O, Suzuki Y, Gallego-Delgado J, Sanjuan G, Lazaro A, Lopez-Parra V, Ortega L, Egido J. Gomez-Guerrero C Fc Receptor Deficiency Confers Protection against Atherosclerosis In ApoE Knockout Mice. Circ Res. 2006; 99: 1188–1196.
17. Deo YM, Graziano RF, Repp R, van de Winkel JG. Clinical significance of IgG Fc receptors and Fc R-directed immunotherapies. Immunol Today. 1997; 18: 127–135.[CrossRef][Medline]
[Order article via Infotrieve]
18. Ravetch JV, Bolland S. IgG Fc receptor. Annu Rev Immunol. 2001; 19: 275–290.[CrossRef][Medline] [Order article via Infotrieve]
19. Park SY, Ueda S, Ohno H, Hamano Y, Tanaka M, Shiratori T, Yamazaki T, Arase H, Karasawa A, Sato S, Ledermann B, Kondo Y, Okumura K, Ra C, Saito T. Resistance of Fc receptor-deficient mice to fatal glomerulonephrits. J Clin Invest. 1998; 102: 1229–1238.[Medline] [Order article via Infotrieve]
20. Suzuki Y, Gomez-Guerrero C, Shirato I, Lopez-Franco O, Gallego-Delgado J, Sanjuan G, Lazaro A, Hernandez-Vargas P, Okumura K, Tomino Y, Ra C, Egido J. Pre-existing glomerular immune complexes induce polymorphonuclear cell recruitment through an Fc receptor-dependent respiratory burst : potential role in the perpetuation of immune nephritis. J Immunol. 2003; 170: 3243–3253.
21. Radeke HH, Janssen-Graalfs I, Sowa EN, Chouchakova N, Skokowa J, Loscher F, Schmidt RE, Heeringa P, Gessner JE. Opposite regulation of type II and III receptors for immunoglobulin G in mouse glomerular mesangial cells and in the induction of anti-glomerular basement membrane (GBM) nephritis. J Biol Chem. 2002; 277: 27535–27544.
22. Gill V, Doig C, Knight D, Love E, Kubes P. Targeting adhesion molecules as a potential mechanism of action for intravenous immunoglobulin. Circulation. 2005; 112: 2031–2039.
23. Konishi H, Katoh Y, Takaya N, Kashiwakura Y, Itoh S, Ra C, Daida H. Platelets activated by collagen through immunoreceptor tyrosine-based activation motif play pivotal role in initiation and generation of neointimal hyperplasia after vascular injury. Circulation. 2002; 105: 912–916.
24. Mineo C, Gormley AK, Yuhanna IS, Osborne-Lawrence S, Gibson LL. Hahner L, Shohet RV, Black S, Salmon JE, Samols D, Karp DR, Thomas GD, Shaul PW. FcRIIB mediates C-reactive protein inhibition of endothelial NO synthase. Circ Res. 2005; 97: 1124–1131.
25. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.
26. Schwedler SB, Amann K, Wernicke K, Krebs A, Nauck M, Wanner C, Potempa LA, Galle J. Native C-reactive protein increases whereas modified c-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2005; 112: 1016–1023.
Related Article:
Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice
Circ. Res. 2006 99: 1188-1196.
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