C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein, with homologs in vertebrates and many invertebrates, that participates in the systemic response to inflammation. Its plasma concentration increases during inflammatory states, a characteristic that has long been employed for clinical purposes. CRP is a pattern recognition molecule, binding to specific molecular configurations that are typically exposed during cell death or found on the surfaces of pathogens. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response. Recently, an association between minor CRP elevation and future major cardiovascular events has been recognized, leading to the recommendation by the Centers for Disease Control and the American Heart Association that patients at intermediate risk of coronary heart disease might benefit from measurement of CRP. This review will largely focus on our current understanding of the structure of CRP, its ligands, the effector molecules with which it interacts, and its apparent functions.

Bacterial recognition by host cells is essential for initiation of infection and the host response. Bacteria interact with host cells via multiple pattern recognition receptors that recognize microbial products or pathogen-associated molecular patterns. In response to this interaction, host cell signaling cascades are activated that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Brain angiogenesis inhibitor 1 (BAI1) is a receptor that recognizes apoptotic cells through its conserved type I thrombospondin repeats and triggers their engulfment through an ELMO1/Dock/Rac1 signaling module. Because thrombospondin repeats in other proteins have been shown to bind bacterial surface components, we hypothesized that BAI1 may also mediate the recognition and clearance of pathogenic bacteria. We found that preincubation of bacteria with recombinant soluble BAI1 ectodomain or knockdown of endogenous BAI1 in primary macrophages significantly reduced binding and internalization of the Gram-negative pathogen Salmonella typhimurium. Conversely, overexpression of BAI1 enhanced attachment and engulfment of Salmonella in macrophages and in heterologous nonphagocytic cells. Bacterial uptake is triggered by the BAI1-mediated activation of Rac through an ELMO/Dock-dependent mechanism, and inhibition of the BAI1/ELMO1 interaction prevents both Rac activation and bacterial uptake. Moreover, inhibition of ELMO1 or Rac function significantly impairs the proinflammatory response to infection. Finally, we show that BAI1 interacts with a variety of Gramnegative, but not Gram-positive, bacteria through recognition of their surface lipopolysaccharide. Together these findings identify BAI1 as a pattern recognition receptor that mediates nonopsonic phagocytosis of Gram-negative bacteria by macrophages and directly affects the host response to infection.innate immunity | lipopolysaccharide-binding | TNF-α

Abstract-C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk and endothelial dysfunction. Whether CRP has direct actions on endothelium and the mechanisms underlying such actions are unknown. Here we show in cultured endothelium that CRP prevents endothelial NO synthase (eNOS) activation by diverse agonists, resulting in the promotion of monocyte adhesion. CRP antagonism of eNOS occurs nongenomically and is attributable to blunted eNOS phosphorylation at Ser1179. Okadaic acid or knockdown of PP2A by short-interference RNA reverses CRP antagonism of eNOS, indicating a key role for the phosphatase. Aggregated IgG, the known ligand for Fc␥ receptors, causes parallel okadaic acid-sensitive loss of eNOS function, Fc␥RIIB expression is demonstrable in endothelium, and heterologous expression studies reveal that CRP antagonism of eNOS requires Fc␥RIIB. In Fc␥RIIB ϩ/ϩ mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance; in contrast, CRP enhances acetylcholine responses in Fc␥RIIB Ϫ/Ϫ mice. Thus Fc␥RIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction. (Circ Res. 2005;97:1124-1131.)Key Words: C-reactive protein Ⅲ endothelial NO synthase Ⅲ Fc␥ receptor Ⅲ PP2A C -reactive protein (CRP) is an acute-phase reactant and a member of the pentraxin family of proteins. Its hepatic synthesis is stimulated by interleukin-6 to yield levels that can rise 500-fold within 24 to 48 hours of the initiation of an inflammatory process. CRP serves as an opsonin and activates complement by binding to C1q. [1][2][3][4] In addition to participating in immune response, CRP has received considerable attention as a risk factor for cardiovascular disease. Although the relative predictive value of CRP versus other risk factors has been variable, the finding that CRP levels correlate with cardiovascular disease has been remarkably consistent across populations. [5][6][7][8][9] CRP is also a risk factor for the progression of subclinical vascular disease and for hypertension. 10,11 Furthermore, a primary effect of CRP on endothelium is plausible because elevated levels are associated with endothelial dysfunction, as evidenced by blunted forearm vascular responses to acetylcholine (Ach), which activates endothelial NO synthase (eNOS) to generate NO on L-arginine conversion to L-citrulline. 12 Potentially consistent with these clinical observations, CRP transgenic mice have exaggerated thrombosis, 13 and CRP blunts eNOS expression and function in cultured endothelial cells. 14,15 However, it has yet to be determined whether CRP has direct effects on vascular endothelium in vivo, and the basis for such effects is unknown.In the present study, we investigated the mechanisms underlying CRP actions on endothelium by testing the hypothesis that CRP attenuates eNOS activation in cultured endothelial cells. The resulting effect on monocyte adhesion was also determined. Because eNOS activation entails ...