gC1qR/p33 Serves as a Molecular Bridge between the Complement and Contact Activation Systems and Is an Important Catalyst in Inflammation

Abstract

The receptor for the globular heads of C1q, gC1qR/p33, is a ubiquitously expressed protein, which is distributed both intracellularly and on the cell-surface protein. In addition to C1q, this molecule also is able to bind several other biologically important plasma ligands, including high-molecular-weight kininogen (HK), factor XII (FXII), and multimeric vitronectin. Previous studies have shown that incubation of FXII, prekallikrein, and HK with gC1qR leads to a zinc-dependent and FXII-dependent conversion of prekallikrein to kallikrein, a requisite for kinin generation. In addition, these studies showed that normal plasma, but not plasma deficient in FXII, PK, or HK, activate upon binding to endothelial cells (EC), and that this activation could be inhibited by antibody to gClqR. In these studies, we show that incubation of serum with microtiter plate bound gC1qR results in complement activation, as evidenced by the binding and activation of C1 and generation of C4d. However, neither Clq-deficient serum nor a truncated form of gC1qR (gC1qRA74-96), supported complement activation. Taken together, the data strongly suggest that at sites of inflammation, such as vasculitis and atherosclerosis, where gC1qR as well as its two important plasma ligands, C1q and HK, have been shown to be simultaneously present, soluble or cell-surface-expressed gC1qR may contribute to the inflammatory process by modulating complement activation, kinin generation, and perhaps even initiation of clotting via the contact system. Based on these and other published data, we propose a model of inflammation in which atherogenic factors (e.g., immune complexes, virus, or bacteria) are perceived not only to convert the endothelium into a procoagulant and proinflammatory surface, but also to induce enhanced expression of cell surface molecules such as gC1qR. Enhanced expression of gC1qR in turn leads to: (i) high-affinity C1q binding and cell production of proinflammatory factors, and (ii) high-affinity HK binding and facilitation of the assembly of contact activation proteins leading to generation of bradykinin and possibly coagulation through activation of FXI.

Regulated complement deposition on the surface of human endothelial cells: Effect of tobacco smoke and shear stress

“…gC1qR is thought to be involved in inflammation via its ability to activate the kinin system on EC [43,44]. More recently, in vitro evidence has been obtained to suggest that gC1qR can directly activate the classical complement cascade by recognizing C1q [20]. Despite the ability of purified gC1qR to activate the classical complement pathway, enhanced C4 activation on EC in the present study did not correlate with changes in gC1qR expression.…”

“…gC1qR is present on the EC surface and was recently shown to participate in classical complement pathway activation [20,21]. Compared to baseline, gC1qR expression increased by approximately 60% (n = 6, P<0.05) in response to shear stress, but was unaffected by TS (0.03 puffs/ml).…”

“…Endothelial cells express several complement receptors, including gC1qR/p33 (gC1qR) [19], which recognizes the globular domain of the first component of the classical complement pathway, C1q. gC1qR has the capacity to directly activate the classical complement pathway [20]. We recently demonstrated classical pathway complement activation on human umbilical vein endothelial cells and on immortalized endothelial cell lines including human bone marrow microvascular endothelial cells.…”

Platelet Mediated Complement Activation

“…The geometry and topography of the three dimensional structure of gC1qR indicates that gC1qR could engage C1q via at least two, if not three, of its globular heads. This could induce the subtle conformational change that is necessary to trigger C1 activation (Ghebrehiwet, Cebada Mora, Tantral, Jesty, and Peerschke 2006). Indeed, recombinant gC1qR has been shown recently to activate C1 ).…”

The contribution of gC1qR/p33 in infection and inflammation

“…Previous studies have shown that native gC1qR purified from Raji cell membranes, or highly purified, and enzyme-free recombinant gC1qR can activate the classical pathway as assessed by hemolytic assay or by solid phase ELISA using gC1qR coated plates and monoclonal antiC4d to detect activation Peterson et al, 1997;Ghebrehiwet et al, 2006). Subsequent experiments showed that the binding site(s) for gC1qR and IgG on the C1q molecule may be identical or perhaps overlap with each other (Peterson et al, 1997) since preincubating serum with gC1qR had a diminished hemolytic activity when further incubated with antibody sensitized sheep erythrocytes.…”