Pentraxins: The L-Type Lectins and the C-Reactive Protein as a Cardiovascular Risk

Abstract

The pentraxins (PTX) are a superfamily of plasma proteins that are involved in innate immunity in invertebrates and vertebrates. They contain L-type lectin folds and require Ca2+ ions for ligand binding. Three of the principal members of the pentraxin family are serum proteins: namely, C-reactive protein (CRP), serum amyloid P component protein (SAP), and female protein (FP). PTX3 (or TSG-14) protein is a cytokine-induced protein that is homologous to CRPs and SAPs, but its function has not yet been determined. Beckmann et al. (1998) identified the superfamily of protein modules comprising the pentraxin families. Beckmann et al. (1998) predicted a jellyroll fold for all members of this superfamily. Pentraxins are made up of five noncovalently bound identical subunits that are arranged in a annular pentameric disc in shape. Proteins with this type of configuration are known as pentraxins. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP), the first innate immunity receptor and serum amyloid P-component (SAP) are the two short pentraxins. Soluble pentraxins act as pattern recognition receptors with a dual role: protection against extracellular microbes and autoimmunity. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). The “long pentraxins” are an emerging family of genes that have conserved in their carboxy-terminal halves a pentraxin domain homologous to the prototypical acute phase protein pentraxins (CRP and SAP component) and acquired novel amino-terminal domains. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues and cells and in particular by innate immunity cells and most notably by dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and in response to proinflammatory signals. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes. Some long pentraxins are expressed in the brain and some are involved in neuronal plasticity and degeneration. PTX3 acts as a functional ancestor of antibodies, recognizing microbes, activating complement, and facilitating pathogen recognition by phagocytes, hence playing a non-redundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility because it acts as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Unlike the classical pentraxins, the PTX3 is expressed after exposure to the inflammatory cytokines to IL-1β and TNF-α, but not to IL-6, in various cell types. PTX3 has been shown to be produced in response to microbial infections, and highly elevated levels have been reported in patients with sepsis (al-Ramadi et al. 2004; Bottazzi et al. 2006; Garlanda et al. 2005; Mantovani et al. 2006).