The soluble pattern recognition receptor pentraxin-3 in innate immunity, inflammation and fertility
Introduction
The innate immune system consists of a cellular and a humoral arm. Components of humoral immunity include members of the complement cascade and soluble pattern recognition receptors (PRR), such as collectins (surfactant protein-A, [SP-A], and SP-D), ficolins, and pentraxins (Bottazzi et al., 2006, Garlanda et al., 2005). These molecules represent functional ancestors of antibodies and play key roles as effectors and modulators of innate resistance in animals and man.
Pentraxins are a superfamily of multifunctional conserved proteins that are characterized by a cyclic multimeric structure and by the presence in their carboxy-terminal of an approximately 200 amino acid conserved “pentraxin domain”, containing an eight amino acid conserved sequence, called the “pentraxin signature”.
C reactive protein (CRP) and serum amyloid P (SAP) components constitute the short pentraxin arm of the superfamily and are acute-phase proteins that regulate innate resistance to microbes and the scavenging of cellular debris and are conserved from mammals to arthropods (Pepys and Hirschfield, 2003). PTX3 and subsequently other long pentraxins were identified in the 1990s as inducible genes or molecules expressed in specific tissues (e.g. neurons, spermatozoa). Long pentraxins have an unrelated, long amino-terminal domain coupled to the carboxy-terminal pentraxin domain, which differ with respect to short pentraxins in their gene organization, chromosomal localization, cellular source, and in their stimuli-inducing and ligand-recognition ability.
PTX3 is the prototypic long pentraxin produced by both resident and innate immune cells in peripheral tissues, in response to inflammatory signals and toll-like receptor (TLR) activation. PTX3 binds to and plays non-redundant protective roles against selected pathogens (Garlanda et al., 2002). PTX3 is endowed with activities unrelated to innate immune responses, such as angiogenesis, extracellular matrix remodelling, and in particular, female fertility.
Section snippets
The long pentraxin PTX3
The human PTX3 gene, localized on human chromosome 3q25, is organized in three exons coding for the leader peptide, the N-terminal domain and the pentraxin domain, respectively. The protein consists of a C-terminal pentraxin domain coupled with an N-terminal portion unrelated to other known proteins. The 45 kDa protomers assemble to form octamers linked by inter-chain disulfide covalent bonds (Bottazzi et al., 1997). PTX3 is N-linked to fucosylated and sialylated complex-type sugars, and
Role of PTX3 in innate immunity and inflammation
The multifunctional properties exerted by PTX3 can be at least in part explained by its capacity to interact with a number of different ligands (Fig. 1), a characteristic shared with CRP and SAP. In particular, PTX3 binds to the complement component C1q, interacting with C1q globular head (Bottazzi et al., 1997, Nauta et al., 2003). The role of PTX3 on the modulation of complement activation is a complex subject and is not completely defined yet. The interaction of PTX3 with C1q results in
Role in self/non-self discrimination
Similarly to CRP and SAP, PTX3 binds to apoptotic cells during late phases of apoptosis (Manfredi et al., 2008). Phosphoethanolamine, phosphocholine, small nuclear ribonucleoproteins and chromatin/nucleolar components, recognized by CRP and/or SAP, redistribute to the plasma membrane during late apoptosis. PTX3 can bind histones, raising the possibility that interaction with nuclear components could actually occur, whereas it does not bind to phosphoethanolamine and phosphocholine.
While PTX3
Role in angiogenesis
PTX3 binds fibroblast growth factor 2 (FGF2), but not other members of the FGF family, through the N-terminal domain (Presta et al., 2007). Interaction between PTX3 and FGF2 prevents FGF2 binding to endothelial cells, leading to inhibition of FGF-dependent cell proliferation in vitro and in vivo. FGF2 plays a key role in the induction of proliferation, migration and survival of vascular SMC. Interaction between PTX3 and FGF2 inhibits SMC proliferation in vitro and reduces intimal hyperplasia
Role of PTX3 in female fertility
In mice, Ptx3 null mutation is associated with a severe defect in female fertility (Salustri et al., 2004, Varani et al., 2002). Infertility of Ptx3 null mutant mice is associated with an abnormal cumulus oophorus in which cumulus cells are uniformly dispersed instead of radiating out from a central oocyte. This abnormal location of granulosa cells is due to defective organization and stability of the extracellular matrix (ECM). The oocyte develops normally in the absence of PTX3, and can be
PTX3 as a marker in human pathology
Similarity to the classic diagnostic CRP has given impetus to efforts aimed at assessing the usefulness of PTX3 as marker in diverse human pathological conditions. Indeed PTX3 behaves as an acute-phase response protein since its blood levels, which are low in normal conditions, increase rapidly and dramatically during inflammatory and infectious conditions, correlating with the severity of the disease. For instance, plasma PTX3 is high in sepsis and septic shock, in acute myocardial infarction,
Concluding remarks
CRP was the first innate immune molecule capable of recognizing microbial moieties to be identified but its function has not been clearly defined. By contrast, gene targeting of the prototypic, evolutionary conserved, long pentraxin PTX3 has unequivocally defined the role of this molecule at the crossroads of innate immunity, inflammation, matrix deposition and female fertility. In particular, increasing evidence suggest the involvement of PTX3 in several steps of female fertility, including
Acknowledgment
This work is supported in part by funding under the European Commission (contracts—LSHM-CT-2004-512040: EMBIC; LSHG-CT-2005-005203: MUGEN), Ministero dell’Istruzione, Università e della Ricerca, Ministero della Salute (Ricerca Finalizzata 2006–2008).
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2016, International Journal of CardiologyCitation Excerpt :Opposing to C reactive protein (CRP) and serum amyloid protein A (SAP) that are produced in the liver in response to IL-6 and considered to be short pentraxins, PTX3 is induced mainly by IL-1 and TNFα in dendritic myeloid cells, peripheral blood leukocytes, endothelial cells, fibroblasts and adipocytes among others and is known as a long pentraxin [1,2]. Several studies have identified PTX3 as an important element in host resistance against fungal, viral and bacterial infection [1–3]. Also high levels of PTX3 have been linked to cardiovascular diseases [4,5] and inflammatory activity in autoimmune disorders such as vasculitis [6].