Perplexity of monocyte responses to C-reactive protein (CRP)

Thromb Haemost 2008; 99: 461–462 C-reactive protein (CRP), a member of the pentraxin family, is one of the prototypic plasma biomarkers of inflammation (1, 2). The physiological roles of CRP in the innate immune response have, however, remained elusive as it possesses both proand anti-inflammatory actions (1, 2). Inflammation is pivotal in all phases of atherosclerosis from the nascent lesion through progression to the culmination in acute coronary syndromes (3). To date, over two dozen large-scale prospective clinical studies have reported that moderate elevations in base-line CRP levels predict, albeit to varying degrees, future cardiovascular disease and death across all levels of lowdensity lipoprotein (LDL) cholesterol and of the Framingham Risk Score (4, 5). CRP has been implicated inmultiple aspects of atherogenesis and plaque vulnerability; however, whether CRP plays a direct causal role in these events remains controversial (reviewed in [6]). For example, transgenic expression of human CRP in apolipoprotein E-deficient mice has been reported to accelerate atherogenesis (7, 8), to show no effect (9) or even to slow atherosclerosis development (10). In vitro, CRP induces release of proinflammatory interleukins IL-1, IL-6, IL-8 and tumor necrosis factor-α NF (11, 12) from human monocytes; promotes monocye adhesion to endothelial cells through upregulation of endothelial adhesion molecules (13, 14) and enhances phagocytosis of oxidized LDL (6). These observations are consistent with the role of monocytes in the initiation and progression of atherosclerosis (3). However, monocytes may have a more complex role in atherogenesis than previously thought. In this issue of Thrombosis and Haemostasis, Hanriot et al. (15) show that CRP modulates expression of genes known to mediate both proand anti-inflammatory responses. These novel observations raise the intriguing possibility that CRP could activate yet unidentified pathways in human monocytes. Using a custom-made 250 oligonucleotide microarray for screening CRP regulated genes in monocytes isolated from apparently healthy men and women (aged 25 to 35 years), Hanriot et al. detected changes in approximately 10% of the genes represented on the microarray. The authors confirm previous studies on CRP induction of pro-inflammatory cytokine gene expression with the exception of TNF, which was unaffected by CRP, and show increased mRNA expression of monocyte chemotactic protein-1 (MCP-1), Gro-β, the chemokine receptors CCR-8 and CXCR-4, and plasminogen activator inhibitor type 2 (PAI-2). In concert with IL-8,MCP-1 andGro-β facilitatemonocyte recruitment and adhesion to endothelial cells, whereas CCR-8 and CXCR-4 mediate monocyte (and macrophage) chemotaxis. The function of PAI-2 appears to be more complex. PAI-2 promotes fibrin deposition in the arterial wall, thereby contributing to progression of the initial lesion, whereas it may stabilize more advanced plaques by inhibiting activation of matrix metalloproteinases, enzymes overexpressed in human atheromata (3). While the concept of CRP’s anti-inflammatory role is not new (reviewed in [1, 2]), Hanriot et al. also report CRP-induced changes in monocyte gene expression that are consistent with suppression of inflammation. Thus, the authors show that CRP attenuates expression of the monocyte/lymphocyte chemotactic proteins MIP-1α and MIP-1β and α2-macroglobulin, which antagonize the actions of the anti-inflammatory cytokine transforming growth factor-β. Protection of mice overexpressing human CRP from allergic encephalomyelitis is mediated through reduction of MIP-1 (16). The most striking finding is that CRP increases expression of the nuclear receptor liver X receptor-α (LXR-α) and one of its target genes the ATP-binding cassette transporter A1 (ABCA1). ABCA1 promotes reverse cholesterol transport from macrophages in atherosclerotic plaques to high density lipoprotein (HDL) and suppresses genes involved in macrophage inflammatory signaling and apoptosis, thereby inhibiting atherosclerosis (17). CRP induction of LXR-α expression and activation is mediated through the high affinity IgG receptor FcγR1 (CD64) and, to lesser a degree, the low affinity IgG receptor FcγRII (CD32), and involves activation of both p42/44MAPK and phosphatidylinositol 3-kinase signaling pathways. A critical issue whether CRP could effectively facilitate reverse cholesterol transport in monocytes (and macrophages) remains to be elucidated. The complexity of LXR-α responses makes it difficult to extrapolate the beneficial or deleterious effects of a target gene in isolation to human pathology when target genes are likely beingmodulated in concert. For example, an-