doi: 10.1161/01.ATV.0000015099.41408.31
© 2002 American Heart Association, Inc.
Editorials |
Pleiotropic Effects of Chemokines in Vascular Lesion Development
From the Massachusetts General Hospital, Center for Immunology and Inflammatory Diseases, Charlestown, Mass.
Correspondence to Robert Gerszten, Massachusetts General Hospital, Center for Immunology and Inflammatory Diseases, Charlestown, MA 02129. E-mail gerszten{at}cvrc.mgh.harvard
In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Roque et al1 studied the response to arterial injury in animals deficient in the monocyte chemoattractant protein-1 (MCP-1) receptor, CCR2. One month after the insult, CCR2 knockout mice showed a profound reduction in intimal area compared with their wild-type littermates. Surprisingly, there was no significant difference in leukocyte accumulation in the arterial wall between the two groups. The authors acknowledge that vascular wounding in mice does not necessarily recapitulate the biology of human atherogenesis or even percutaneous interventions. Nonetheless, the results of their studies are extremely provocative. These unanticipated findings contrast with our preconceived notions of direct links between chemokines, leukocyte accumulation, and vascular lesions.
See page 554
The prevailing dogma suggests that aberrant chemokine production is induced by noxious stimuli such as oxidized LDL,2 or as in this case, by mechanical forces.3 Lesion development is then propagated by chemokine-triggered leukocyte accumulation via two mechanisms, enhanced firm adhesion and chemotaxis. In the bloodstream, chemokines play a critical role in the initial step of leukocyte infiltration, within seconds converting leukocyte tethering or rolling on the vascular endothelium to firm arrest via the activation of leukocyte surface integrins.4,5 As chemoattractants, chemokines subsequently play an important role in the directional migration of leukocytes through tissues.
Although chemokines were originally described for their role in host immunity, a growing body of evidence suggests a broader range of biological targets than was first appreciated. These data provide possible clues as to why CCR2-deficient animals might have comparable leukocyte recruitment after acute injury, yet markedly diminished lesions. Chemokine-directed cell movement is an underlying theme. However, both chemokine ligands and their receptors are clearly expressed by nonimmune cells and orchestrate a number of unanticipated responses. For example, mice deficient in the chemokine stromal–derived factor-1,6 or its receptor CXCR4,7,8 have lethal defects of the cardiac intraventricular septum. Analysis of the cerebellums from these animals also suggests aberrant migration and abnormal clustering of neurons. Even in the vessel wall, the story is not as simple as it seems at first glance. Recent data suggest that several chemokines trigger platelet aggregation at physiological relevant concentrations, a potential mechanism for enhanced cross-talk between the inflammatory and coagulation cascades.9 Several chemokines such as interleukin-8 (IL-8) have potent angiogenic properties.10 This may contribute to the neovascularization that enhances lesion development. A growing body of literature also suggests a role for chemokines in the trafficking of circulating non-leukocytic cells, such as fibrocytes.11 These primitive cells appear to rapidly home to tissues after injury.
Recent investigation into chemokine-triggered cell signaling has also questioned our assumptions that chemokines function solely to modulate cell adherence or movement. These data also shed light on the unanticipated findings in the article by Roque et al.1 Chemokines activate intracellular signaling pathways via specific G protein–coupled receptors. The relevant downstream intracellular signaling mechanisms remain poorly understood. However, recent knockout studies have convincingly shown that one signaling axis involves the phosphoinositide 3-kinase (PI 3-K) family. Loss of the p110
PI 3-K isoform in particular impairs the ability of neutrophils and peritoneal macrophages to migrate.12–14 Subsequent signal transduction events known to be downstream of PI 3-K, which are also activated by chemokines, include the phosphorylation of Akt15 and glycogen synthase kinase-3,16 among others. Thus, the intracellular machinery that chemokines harness to modulate movement has also been implicated in a host of other cellular processes, particularly cell survival and proliferation. Chemokine-enhanced survival might even play a role in the persistence of monocytes as tissue macrophages
So what are the most likely explanations for the discordance between leukocyte homing versus lesion development found by Roque et al?1 A key vascular wall constituent not addressed above is the smooth muscle cell. Indeed, the authors of this article have previously shown that MCP-1 can induce tissue factor expression in this cell type.17 CCR2 might therefore be mediating an activation or survival/proliferation signal to these cells. The authors note that in vitro studies to date which have assessed chemokine-induced smooth muscle cell proliferation are not definitive. Undoubtedly, the same chemokines might have considerably different effects in the complex milieu of the vessel wall. Alternatively, the effect on smooth muscle cells may be indirect, via CCR2-dependent signals conferred by leukocytes. While neutrophils or monocytes seem to be recruited comparably to the wild-type versus knockout vessels, their activation state may differ drastically. Activated leukocytes might secrete signals or transduce them via integrins in a CCR2-dependent manner. Unfortunately, reliable markers of monocyte activation in this regard remain elusive.
The thoughtful work by Roque et al1 make us redouble our efforts to understand the protean effects of chemokines on multiple cell types. It also raises interesting questions regarding MCP-1, the chemokine most associated with monocyte biology. In an explanted atherosclerotic carotid artery model, Huo et al18 recently found that neither anti-MCP-1 antibodies nor MCP-1 receptor antagonists prevented monocyte adhesion to vascular endothelium. In contrast, antagonists of the murine IL-8 homologue, classically a neutrophil chemokine, had striking effects on monocyte adhesion in their system. Previous in vitro studies had also suggested that CXC chemokines, such as IL-8, could potently trigger monocyte arrest to endothelial cells.5 In this context, a more heretical reader of the work by Roque et al1 might suggest that CCR2 plays no role in the initial steps of leukocyte accumulation, at least in some models. Rather, CCR2 provides an entirely different type of signal as noted above—potentially for monocyte/macrophage activation, survival, or by conferring a signal to an unanticipated cellular target.
Roque et al1 allude to a future series of experiments to dissect the relevant players in their vascular injury model. Specifically, they propose bone marrow transplantation studies between CCR2 knockout and wild-type mice and, vice versa, to parse out leukocyte versus non-leukocyte contributions. Their future studies may well cast more doubt on the "prevailing wisdom" about chemokines, or to paraphrase Mark Twain, help us question "what we do know that ain’t necessarily so."
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