doi: 10.1161/CIRCRESAHA.107.155838
© 2007 American Heart Association, Inc.
Editorials |
Targeting Interferon-
to Treat Atherosclerosis
From the Heart Institute (I.G.), Hadassah University Hospital, Jerusalem, Israel; and Immunology and Vascular Research Divisions (A.H.L.), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Andrew H. Lichtman, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB 752N, Boston, MA 02115. E-mail lichtman{at}rics.bwh.harvard.edu
See related article, pages 348–356
Key Words: atherosclerosis • cytokines • interferon-
• gene therapy
The chronic inflammatory nature of atherosclerotic disease is now widely appreciated. Abnormal deposition and oxidative modification of serum lipoproteins in arterial walls stimulates the recruitment of monocytes and their conversion into foam cells. Concurrently, both innate and adaptive immune responses are induced. Cytokines and growth factors produced as part of these responses lead to the remodeling of the arterial wall that typifies atherosclerotic lesions, including SMC accumulation and collagenous matrix deposition in the intima.1 The predominant inflammatory cells found in the atherosclerotic plaques are macrophages and T lymphocytes.2 The majority of T lymphocytes in atherosclerotic lesions are CD4+ T-helper cells expressing markers of activation.3 These activated T lymphocytes have been shown to be important in propagating the inflammatory processes that enhance lesion development.4,5 The majority of these T cells have a phenotype characteristic of the proinflammatory T-helper 1 (Th1) subset, and Th1-mediated immune responses have been shown to correlate with the development of atherosclerosis in mouse models.6–8
The signature cytokine produced by Th1 cells is interferon (IFN). Immunohistochemical and in situ hybridization studies indicate that IFN is present in human atherosclerotic plaques.2,9–11 Numerous studies in mice have demonstrated a central role of IFN in atherosclerosis. Genetic ablation of IFN or IFN receptor (IFNR) expression in mice significantly reduces atherosclerosis,12,13 whereas administration of exogenous IFN potentiates atherosclerosis.14 IFN has many different biologic effects that contribute to lesion development, including enhancement of antigen presenting capabilities of endothelium and macrophages, enhancement of inflammatory cell recruitment via upregulation of endothelial adhesion molecules, stimulation of proinflammatory cytokine and chemokine secretion by macrophages, production of reactive oxygen species by macrophages, and the inhibition of cholesterol efflux from foam cells.15 IFN also contributes to destabilization of mature lesions by blocking smooth muscle cell (SMC) proliferation and collagen synthesis and by stimulating matrix metalloproteinase synthesis by macrophages.
Given the central role of IFN in atherosclerotic-plaque pathology, therapeutically targeting this cytokine could reduce the atherosclerotic burden and/or enhance the stability of plaques. The study by Koga et al in the current issue of Circulation Research16 addresses this option in a mouse model. The study elegantly demonstrates that IFN neutralization, by repeated injections of a plasmid encoding a soluble INF-R construct (sIFNR), reduces lesion progression. In 1 experiment, apolipoprotein E (apoE)-deficient mice were fed a high-fat diet for 8 weeks and received 2 intramuscular injections of control or sIFNR-encoding plasmid DNA after 4 and 6 weeks of the diet regimen before euthanasia. The efficacy of the sIFNR treatment in neutralizing IFN was confirmed in a biological assay, and the effects of the treatment on aortic lesion size and phenotypes were assessed. The treatment was found to significantly reduce lesion size. Furthermore, the plaque burden reduction was accompanied by a change to a more stable phenotype with reduced lipid and macrophages and increased SMCs and collagen deposition. In support of a direct affect of IFN blocking, reduced phosphorylation of Stat1, a downstream signaling molecule activated through the IFNR, was seen in the lesions of the treated mice. Koga et al also provide some mechanistic explanation for these findings. They show that sIFNR treatment downregulates lesional gene expression of the proinflammatory molecules interleukin-1β, interleukin-6, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1
. All of these molecules have been shown to be important in the development of the atherosclerotic lesion. In addition, the treatment reduced the gene expression of matrix metalloproteinase-9 and -13, enzymes important in extracellular matrix degradation, while upregulating procollagen type I. These findings provide a plausible explanation for the stabilization of the plaque. They also show that CD40 and CD40L, which exert proatherogenic effects in mice, are downregulated in the lesions of the treated mice.
Although it is now well established that IFN plays a central role in the propagation of atherosclerosis and genetic ablation significantly reduces atherosclerosis, this is the first published study that targets IFN in a pharmacological manner (using a gene transfer technology) to treat atherosclerosis. The use of sIFNR gene transfer and the effects of this approach on atherosclerotic lesion development and phenotype are of significant interest. This novel approach has several advantages. In experimental animals it avoids developmental compensations for mutant genes that may arise in gene knock out mice. The use of plasmid injection allows some control over the time course of IFN neutralization. Importantly, gene transfer is a potential treatment strategy in humans, and therefore this study helps in defines the feasibility of targeting a proatherogenic cytokine.
Although the prospect of targeting INF- as a potential therapeutic avenue for atherosclerosis, as suggested by this article, is very appealing, several issues must be addressed before such an approach can be considered in the clinical arena. In a second experiment focusing on what happens after treatment cessation, Koga et al fed the apoE–/– mice a high-fat diet for 16 weeks, and sIFNR treatment was administered to 1 group at 4, 6, 8, and 12 weeks and administered to another group only at 4 and 6 weeks. In this experiment, lesion progression resumed, possibly even at a faster rate than in mock-treated animals, after sIFNR treatment was stopped. This raises concerns about the potential limitations of cytokine blockade in general for the treatment of atherosclerosis, because temporary blockade of plaque-based inflammation apparently does not effectively remove the stimuli driving the inflammation or the cells that respond to these stimuli. Of course, IFN has a central role in the function of the adaptive immune response, and long-term systemic inhibition of IFN may result in increased susceptibility to intracellular infections and possibly neoplasia. As suggested by the authors, it is very appealing to consider local therapeutic avenues such as local delivery of recombinant sIFNR protein using nanoparticles, thus avoiding the possible systemic side effects.
Another important finding of this study is the potential stabilizing affect of sIFNR treatment on the atherosclerotic plaque. As the majority of acute coronary events are postulated to occur when unstable plaques rupture, stabilization of the lesion is of significant clinical importance. Koga et al demonstrated that sIFNR-treated animals had a more stable phenotype, with reduced inflammatory cells and increased collagen and SMC content. Indeed, IFN has been shown to reduce collagen type I deposition by SMCs affecting the extracellular matrix17,18 and primes SMCs to Fas-induced apoptosis,19 undermining the stability of the atherosclerotic plaque and causing reduced stability of the lesion. However, there is evidence to suggest that IFN may have the reverse effect on vascular remodeling. IFN may directly cause SMC proliferation and activation,20 inhibit SMC apoptosis, and increase formation of neointimal proliferation after vascular injury.21 Indeed, in a recent publication by the same group, IFN blockade using the same sIFNR agent used in the present study, caused reduced proliferation of intimal SMC, attenuating neointima formation in a rat model of vascular injury.22 Further work will be required to understand these conflicting effects of IFN blockade on neointimal SMC accumulation in different vascular pathologies.
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Acknowledgments |
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Sources of Funding
This work was supported by NIH grant R01 HL87282 (to A.H.L).
Disclosures
None.
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References |
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Related Article:
Function Blocking in ApoE-Knockout Mice
Circ. Res. 2007 101: 348-356.
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