doi: 10.1161/hq0302.104847
© 2002 American Heart Association, Inc.
Editorials |
Leukocyte Recruitment Into Developing Atherosclerotic Lesions
The Complex Interaction Between Multiple Molecules Keeps Getting More Complex
From the Department of Pathobiology, University of Washington, Seattle. E-mail ssmjm@u.washington.edu
Correspondence to Dr. Michael Rosenfeld, Department of Pathobiology, Box 353410, University of Washington, Seattle, WA 98195. E-mail ssmjm{at}u.washington.edu
Afew years ago, I was asked to give a series of lectures to our second-year medical students on basic inflammatory mechanisms. I was taking the place of the late Russell Ross, who had given these lectures for many years. Among the teaching materials Russ had collected was a videotape generated from a 16-mm movie made in the 1940s. The movie showed leukocytes rolling, adhering, and migrating through capillaries in response to an inflammatory stimulus in a rabbit ear chamber. I used this videotape to illustrate the basic steps in a classical inflammatory response but also to introduce to the students the remarkable complexity of the molecular interactions underlying each step in leukocyte recruitment into inflamed tissues. We have come a long way in delineating the nature of these molecular interactions since the 1940s. We now use in vitro adhesion assays and microscopic techniques such as intravital microscopy, coupled with antibodies and receptor antagonists designed to specify which candidate adhesion molecules, counter receptors, and chemokines mediate leukocyte recruitment1–7 These have provided a basic molecular paradigm for the rolling, activation, arrest, adhesion, and transmigration of leukocytes. L and P selectins appear to be primarily responsible for the initial capture of cells from the flowing blood, E and P selectins for mediating rolling, and ß2 integrins, ICAM-1, and PECAM-1 for adhesion and transmigration.8–10 In addition, products of the arachidonate and complement cascades and chemokines, a large family of small peptides that activate leukocytes via binding to G protein–coupled receptors, also seem to play fundamental roles in the recruitment process.11–13
See page 443
Most of our current knowledge of the molecular mediators of leukocyte recruitment has been derived from adhesion assays and studies of the microvasculature. Determining whether the same molecules are involved in recruiting leukocytes into atherosclerotic lesions in the muscular arteries has been more problematic. There is extensive evidence that many of these molecules are expressed by cells in human and experimental atherosclerotic lesions14–23 and that expression of adhesion molecules such as VCAM-1 is temporally related to lesion initiation and progression in animal models.22,24 Furthermore, studies of transgenic mice or mice with targeted mutations have provided some insights into which of these molecules play roles in the atherogenic process. In particular, these studies have so far shown that E and P selectins, ICAM-1, MCP-1, and its receptor CCR2, as well as the IL-8 receptor CXCR2, seem to mediate recruitment of leukocytes into atherosclerotic lesions in hyperlipidemic mice.25–34 However, the in vivo studies have also clearly demonstrated the presence of redundant mechanisms, as in no case has there been a complete ablation of lesion development in the absence of any one of these molecules. A look at the increasing list of known chemokines and the lack of specificity with which they bind to the CCR and CXCR receptors12,13 further emphasizes the extent to which redundancy exists in this system and again points to the underlying complexity of the molecular interactions supporting leukocyte recruitment.
In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Aiello et al35 provide direct evidence that leukotrienes also contribute to monocyte infiltration into atherosclerotic lesions. They convincingly demonstrate that a specific LTB4 receptor antagonist significantly inhibits atherosclerotic lesion development and reduces the macrophage component of the lesions in apoE-/- and LDLR-/- mice. Thus, these investigators have added a new level of complexity to the equation. Although it has been known for many years that LTB4 plays a significant role in the recruitment of neutrophils and that macrophages express LTB4 receptors,36 demonstrating a role for LTB4 in atherosclerosis has awaited the development of highly specific LTB4 receptor antagonists and the availability of convenient models in which to test their effects.
Perhaps it is not surprising that LTB4 plays a role in the atherogenic process being a product of the 5-lipoxygenase pathway. We have speculated for many years about the potential roles of arachidonic acid metabolites in atherosclerosis, in particular those generated by 12/15 lipoxygenase. These range from the oxidation of LDL37,38 to stimulating intracellular signal transduction.39 There is also in vitro evidence that products of 12/15 lipoxygenase mediate leukocyte adhesion.40–42 Furthermore, recent data in mice with disruption of the 12/15 lipoxygenase gene or overexpressing 12/15 lipoxygenase provide direct evidence that products of these enzymes contribute to the atherogenic process.43–46 Despite evidence of the formation of LTB4 in atherosclerotic lesions,47 to date there have been very few previous studies suggesting that products of 5-lipoxygenase play any role in atherogenesis.48,49
Aiello et al35 provide two additional and intriguing observations that suggest that LTB4 mediates leukocyte recruitment into atherosclerotic lesions by indirect mechanisms. First, they demonstrate that the LTB4 receptor antagonist inhibits the LTB4-induced upregulation of CD11b expression in circulating monocytes from the treated mice. CD11b is the ß2 integrin component of the CD11/CD18 complex on monocytes that mediates binding to ICAM-1 as well as to fibrinogen and heparin.49 It is currently unclear to what extent ICAM-1 contributes to lesion formation as targeted knockout of ICAM-1 in mice only has a modest effect on inhibiting lesion formation.27 Furthermore, Kubo et al50 have shown that bone marrow transplantation with CD11b-deficient cells does not inhibit lesion formation in LDLR-/- mice. Thus, it seems unlikely that this effect of LTB4 plays a significant role in recruiting monocytes into lesions in mice.
The second observation is much more compelling. Aiello et al35 have also shown that in mice simultaneously deficient in MCP-1 and apoE, there is no inhibitory effect of the LTB4 receptor antagonist. There are two possible interpretations for this observation. The first is rather trivial and suggests that, in the MCP-1 deficient mice, the absence of MCP-1 already reduces monocyte recruitment to the point where any other inhibitory mechanism has no additional effect. This is somewhat unlikely given the degree of redundancy in the chemokine system and the fact that CCR2 deficient mice exhibit a reduced rate of lesion initiation with catch-up at later time points.32 The more interesting possibility is that there is cross-talk between MCP-1 and LTB4 signaling. For example, LTB4 may induce expression of MCP-1 and thus functions to recruit monocytes not via a direct chemotactic response, but through MCP-1. Unfortunately, Aiello et al35 don’t provide any evidence that the LTB4 receptor antagonist inhibits MCP-1 expression or conversely that LTB4 induces MCP-1 in the apoE-/- or LDLR-/- mice. However, as cited by the Aiello et al,35 it has been shown that the same LTB4 receptor antagonist inhibits neutrophil and macrophage recruitment into the peritoneum of mice with cecal ligation and puncture and reduces the levels of MCP-1 in the peritoneal cavity of these mice.51 Furthermore, administration of MCP-1 elevates the levels of LTB4 in the peritoneum and stimulates the production of LTB4 in peritoneal macrophages in vitro. It is highly likely, therefore, that a similar pattern of cross-talk occurs in the artery wall.
The observations of Aiello et al35 suggest a new direction for studies of monocyte recruitment as it appears that there is now another set of molecules to add to our list of those mediating leukocyte recruitment into atherosclerotic lesions, the leukotrienes. Regardless of whether they exert a direct chemotactic response or function through the induction of adhesion molecules and chemokines such as MCP-1, it is clear that what was already a complex system has just gotten a bit more complex.
References
1.
Carlos TM, Schwartz B, Kovach NL, Yee E, Rosa M, Osborn L, Chi-Rosso G, Newman B, Lobb R, Rosso M. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood. 1990; 76: 965–970.
2. Jones DA, Abbassi O, McIntire LV, McEver RP, Smith CW. P-selectin mediates neutrophil rolling on histamine stimulated endothelial cells. Biophys J. 1993; 65: 1560–1569.[Medline] [Order article via Infotrieve]
3.
Luscinskas FW, Kansas GS, Ding H, Pizcueta P, Schleiffenbaum BE, Tedder TF, Gimbrone MAJr. Monocyte rolling, arrest and spreading on IL-4-activated vascular endothelium under flow is mediated via sequential action of L-selectin, ß1-integrins, and ß2-integrins. J Cell Biol. 1994; 125: 1417–1427.
4. Pizcueta P, Luscinskas FW. Monoclonal antibody blockade of L-selectin inhibits mononuclear leukocyte recruitment to inflammatory sites in vivo. Am J Pathol. 1994; 145: 461–469.[Abstract]
5. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rosenzweig A. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999; 398: 718–723.[CrossRef][Medline] [Order article via Infotrieve]
6.
Ley K, Bullard DC, Arbones ML, Bosse R, Vestweber D, Tedder TF, Beaudet AL. Sequential contribution of L- and P-selectin to leukocyte rolling in vivo. J Exp Med. 1995; 181: 669–675.
7.
Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K. Direct demonstration of P-selectin and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circ Res. 1999; 84: 1237–1244.
8. Tailor A, Granger DN. Role of adhesion molecules in vascular regulation and damage. Curr Hypertens Rep. 2000; 2: 78–83.[Medline] [Order article via Infotrieve]
9. Kubes P, Ward PA. Leukocyte recruitment and the acute inflammatory response. Brain Pathol. 2000; 10: 127–135.[Medline] [Order article via Infotrieve]
10. Steeber DA, Tedder TF. Adhesion molecule cascade direct lymphocyte recirculation and leukocyte migration during inflammation. Immunol Res. 2001; 22: 299–317.[CrossRef]
11. Terkeltaub R, Boisvert WA, Curtiss LK. Chemokines and atherosclerosis. Curr Opin Lipidol. 1998; 9: 397–405.[CrossRef][Medline] [Order article via Infotrieve]
12.
Loetscher P, Clark-Lewis I. Agonistic and antagonistic activities of chemokines. J Leukoc Biol. 2001; 69: 881–884.
13. Baggiolini M. Chemokines in pathology and medicine. J Int Med. 2001; 250: 91–104.[CrossRef][Medline] [Order article via Infotrieve]
14.
Yla-Herttuala S, Lipton BA, Rosenfeld ME, Sarkioja T, Yoshimura T, Leonard EJ, Witztum JL, Steinberg D. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A. 1991; 88: 5252–5256.
15.
Cybulsky MI, Gimbron MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991; 251: 788–791.
16. Poston RN, Haskard DO, Coucher JR, Gall NP, Johnson-Tidey RR. Expression of intercellular adhesion molecule-1 in atherosclerotic plaques. Am J Pathol. 1992; 140: 665–673.[Abstract]
17. Van der Wal AC, Das PK, Tigges AJ, Becker AE. Adhesion molecules on the endothelium and mononuclear cells in human atherosclerotic lesions. Am J Pathol. 1992; 141: 1427–1433.[Abstract]
18. O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques: implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest. 1993; 92: 945–951.[Medline] [Order article via Infotrieve]
19.
Richardson M, Hadcock SJ, DeReske M, Cibulsky MI. Increased expression in vivo of VCAM-1 and E-selectin by the aortic endothelium of normolipidemic and hyperlipidemic diabetic rabbits. Arterioscler Thromb. 1994; 14: 760–769.
20. Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN. Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques: coexpression with intercellular adhesion molecule-1. Am J Pathol. 1994; 144: 952–961.[Abstract]
21. Pattison JM, Nelson PJ, Huie P, Sibley RK, Krensky AM. RANTES chemokine expression in transplant-associated accelerated atherosclerosis. J Heart Lung Transplant. 1996; 15: 1194–1199.[Medline] [Order article via Infotrieve]
22.
Nakashima Y, Raines EW, Plump AS, e Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the apo E-deficient mouse. Arterioscler Thromb Vasc Biol. 1998; 18: 842–851.
23.
Iilyama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD, Cybulsky MI. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res. 1999; 85: 199–207.
24.
Li H, Cybulsky MI, Gimbrone MA, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule in rabbit endothelium. Arterioscler Thromb. 1993; 13: 197–204.
25. Nageh MF, Sandberg ET, Marotti KR, Lin AH, Melchior EP, Bullard DC, Beaudet AL. Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 1997; 80: 810–818.
26. Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest. 1997; 99: 1037–1043.[Medline] [Order article via Infotrieve]
27.
Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-selectin or ICAM-1 deficiency substantially protects against atherosclerosis in apo E deficient mice. J Exp Med. 2000; 191: 189–194.
28. Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. Combined role of P- and E-selectins in atherosclerosis. J Clin Invest. 1998; 102: 145–152.[Medline] [Order article via Infotrieve]
29.
Dong ZM, Brown AA, Wagner DD. Prominent role of P-selectin in the development of advanced atherosclerosis in apo E-deficient mice. Circulation. 2000; 101: 2290–2295.
30.
Aiello R, Bourassa P, Lindsey S, Weng W, Natoli E, Rollins BJ, Milos PM. Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol. 1999; 19: 1518–1525.
31. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractantprotein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Molecular Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]
32. Boring L, Gosling J, Cleary M, Charo I. Decreased lesion formation in CCR2-/- mice reveals a role of chemokines in the initiation of atherosclerosis. Nature. 1998; 394: 894–897.[CrossRef][Medline] [Order article via Infotrieve]
33. Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG, Rollins BJ, Charo IF. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest. 1999; 103: 773–778.[Medline] [Order article via Infotrieve]
34. Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest. 1998; 101: 353–363.[Medline] [Order article via Infotrieve]
35.
Aiello RJ, Bourassa P-A, Lindsey S, Weng W, Freeman A, Showell HJ. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol. 2002; 22: 443–449.
36.
Cristol JP, Provencal B, Borgeat P, Sirois P. Characterization of leukotriene B4 binding sites on guinea pig lung macrophages. J Pharmacol Exp Ther. 1988; 247: 1199–1203.
37. Yamashita H, Nakamura A, Noguchi N, Niki E, Kuhn H. Oxidation of low density lipoprotein and plasma by 15-lipoxygenase and free radicals. FEBS Lett. 1999; 26: 287–290.
38. Cathcart MK, Folcik VA. Lipoxygenases and atherosclerosis: protection versus pathogenesis. Free Radic Biol Med. 2000; 15: 1726–1734.
39.
Natarajan R, Reddy MA, Malik KU, Fatima S, Khan BV. Signaling mechanism of nuclear factor-kappa B–mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21: 1408–1413.
40. Hedrick CC, Kim MD, Natarajan RD, Nadle JL. 12- Lipoxygenase products increase monocyte: endothelial interactions. Adv Exp Med Biol. 1999; 469: 455–460.[Medline] [Order article via Infotrieve]
41. Viita H, Sen CK, Roy S, Siljamaki T, Nikkari T, Yla-Herttuala S. High expression of human 15-lipoxygenase induces NF-kappB-mediated expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and T-cell adhesion on human endothelial cells. Antioxid Redox Signal. 1999; 1: 83–96.[Medline] [Order article via Infotrieve]
42.
Patricia MK, Kim JA, Harper CM, Shih PT, Berliner JA, Natarajan R, Nadler JL, Hedrick CC. Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 2615–2622.
43. Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999; 103: 1487–1488.[Medline] [Order article via Infotrieve]
44.
Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H, Sigal E. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20: 2100–2105.
45.
Cyrus T, Pratico D, Zhao L, Witztum JL, Rader DJ, Rokach J, FitzGerald GA, Funk CD. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice. Circulation. 2001; 103: 2277–2282.
46.
George J, Afek A, Shaish A, Levkovitz H, Bloom N, Cyrus T, Zhao L, Funk CD, Sigal E, Harats D. 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation. 2001; 104: 1646–1650.
47. De Caterina R, Mazzone A, Giannessi D, Sicari R, Pelosi W, Lazzerini G, Azzara A, Forder R, Carey F, Caruso D. Leukotiene B4 production in human atherosclerotic plaques. Biomed Biochim Acta. 1988; 47: S182–185.[Medline] [Order article via Infotrieve]
48.
Devaraj S, Jialal I. Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase. Arterioscler Thromb Vasc Biol. 1999; 19: 1125–1133.
49. Weber C, Erl W, Weber KS, Weber PC. Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions. Clin Chem Lab Med. 1999; 37: 243–251.[CrossRef][Medline] [Order article via Infotrieve]
50.
Kubo N, Boisvert WA, Ballantyne CM, Curtiss LK. Leukocyte CD11b expression is not essential for the development of atherosclerosis in mice. J Lipid Res. 2000; 41: 1060–1066.
51.
Matsukawa A, Hogaboam CM, Lukacs NW, Lincoln PM, Strieter RM, Kunkel SL. Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4. J Immunol. 1999; 163: 6148–6154.
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