Pattern recognition by pentraxins

Abstract

Pentraxins are a family of evolutionarily conserved pattern-recognition proteins that are made up of five identical subunits. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver while PTX3 is produced in a variety of tissues during inflammation. The main functions of short pentraxins are to recognize a variety of pathogenic agents and then to either eliminate them or neutralize their harmful effects by utilizing the complement pathways and macrophages in the host. CRP binds to modified low-density lipoproteins, bacterial polysaccharides, apoptotic cells, and nuclear materials. By virtue of these recognition functions, CRP participates in the resolution of cardiovascular, infectious, and autoimmune diseases. SAP recognizes carbohydrates, nuclear substances, and amyloid fibrils and thus participates in the resolution of infectious diseases, autoimmunity, and amyloidosis. PTX3 interacts with several ligands, including growth factors, extracellular matrix component and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes. In addition, data in gene-targeted mice show that PTX3 is essential in female fertility, participating in the assembly of the cumulus oophorus extracellular matrix. PTX3 is therefore a nonredundant component of the humoral arm of innate immunity as well as a tuner of inflammation. Thus, in conjunction with the other components of innate immunity, the pentraxins use their pattern-recognition property for the benefit of the host.

Figure 1

The long pentraxin PTX3 acts as a soluble multifunctional protein. The multifunctional properties of PTX3 involve interaction with a number of different ligands such as the complement component C1q, the growth factor FGF2, the extracellular matrix component TSG-6, late apoptotic cells and outer membrane proteins of Gram-negative bacteria. Interaction of PTX3 with its ligands is essential for the multifunctional properties exerted by this pentraxin in microbial recognition, discrimination between self and nonself, tissue remodelling, and tuning of the inflammatory response. Binding of PTX3 to plastic-immobilized C1q induces activation of the classical complement pathway and the angiogenic activity of FGF2 in vivo and in vitro is blocked by PTX3. In addition PTX3 is an integral component of the extracellular matrix and plays a crucial role in female fertility.

Figure 2

Pentraxins in innate immunity. Inflammation and microbial sensing induce both local and systemic responses characterized by the production of different members of the pentraxin family. Systemic response involves production by the liver of the prototypic short pentraxin CRP and SAP while local response involves production by macrophages, dendritic cells and endothelial cells of the long pentraxin PTX3. Both short and long pentraxins recognize pathogens, activate the classical complement cascade, participate in tissue remodelling and in self/ non self discrimination, outlining the role of these proteins in the amplification of innate immunity and in the modulation of inflammatory response.