Pentraxine 3

Pentraxins are a family of evolutionarily highly conserved proteins that are characterized by a cyclic multimeric structure (Garlanda C et al. 2005). Alongside the molecules of the complement cascade, pentraxins are among the main players in the humoral arm of innate immunity. Alongside the collectins, the ficolins, they act as soluble pattern recognition molecules(PRMs) (Wu Q et al. 2020).

Among the PRMs, pentraxins belong to a superfamily of evolutionarily conserved, soluble and multifunctional innate pattern recognition proteins with regulatory properties in inflammatory states. The superfamily of pentraxins branches into short pentraxins and long pentraxins. The short pentraxins include the C-reactive protein (CRP) and the serum amyloid P component (SAP). The long pentraxin subfamily includes: neuronal pentraxin 1 (NP1 or NPTX1), neuronal pentraxin 2 (NP2 or NPTX2), neuronal pentraxin receptor (NPR), pentraxin 3 (PTX3) and pentraxin 4 (PTX4) (Wu Q et al. 2020).

In contrast to the classical short pentraxins C-reactive protein(CRP) and serum amyloid P component(SAP), which are predominantly synthesized by hepatocytes and distributed throughout the body via the bloodstream, the prototypical long pentraxin 3 (PTX3) can be produced by a variety of cell types in peripheral tissues. Although PTX3 was originally described as a product of vascular endothelial cells and fibroblasts, it is primarily secreted by macrophages and myeloid dendritic cells (DCs). In addition, it is present in a functional "ready" form stored in granules of neutrophils and is immediately released upon microbial stimulation. MiRNAs, cytokines, transcription factors and drugs can modulate the expression level of PTX3 (Nauta AJ et al. 2005; Giacomini A et al. 2018;Yu LM et al. 2018).

PTX3 plays an essential role in the regulation of innate immunity by exerting opsonic activity, modulating complement activation and forming and regulating neutrophil extracellular traps (NETs) (Wu Q et al. 2020). PTX3 binds with high affinity and specificity to fibroblast growth factor 2 (FGF-2), an angiogenic factor of the fibroblast growth factor (FGF) family, and acts as a natural angiogenesis inhibitor (Rusnati M et al. 2004). In addition, PTX3 was able to bind to fibrinogen/fibrin and plasminogen at acidic pH and increase plasmin-mediated fibrinolysis, which is a prerequisite for adequate repair.

Notably, PTX3 is overexpressed in many tumor types, such as breast cancer, prostate cancer, lung cancer, hepatocellular carcinoma, glioma, melanoma and liposarcoma (Wu Q et al. 2020).

PTX3 has also been shown to be involved in the development, angiogenesis, metastatic spread and immunomodulation of tumors (Giacomini A et al. 2018).

Genetic variants of PTX3: The human PTX3 gene is located on chromosome 3q25, is 1861 base pairs long and has three exons and two introns. The first and second exons encode the leader peptide and the N-terminal domain, while the third exon encodes the C-terminal pentraxin domain.

Single nucleotide polymorphisms (SNPs) in PTX3 are closely associated with the susceptibility and development of some infectious and neoplastic diseases. In patients with chronic obstructive pulmonary disease (COPD), the rs1840680 AA genotype is significantly associated with an increased risk of pulmonary aspergillosis. Conversely, the rs3816527 AA genotype may be associated with a lower risk of pulmonary cryptococcal infections ((Wu Q et al. 2020).

It is noteworthy that PTX3 can bind to different ligands/receptors with different structures and sources, which may depend on its structural properties. The disulfide-linked tetramer and the tetramer consisting of a dimer of dimers in the N-terminal domain of the PTX3 protein were each able to bind to a single FGF-2 molecule. FGF-2 is a proangiogenic factor, and PTX3 could act as an angiogenic inhibitor by antagonizing FGF-2 (Inforzato A et al. 2010).

1. Garlanda C et al. (2005) Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 23: 337-366
2. Giacomini A et al. (2018) Long pentraxin 3: a novel multifaceted player in cancer. Biochim Biophys. Acta Rev. Cancer 1869: 53-63
3. Inforzato A et al. (2010) The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2. J Biol Chem 285: 17681-17692
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5. Nauta AJ et al. (2005) Human renal epithelial cells produce the long pentraxin PTX3. Kidney Int 67: 543-553
6. Rusnati M et al. (2004) Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis. Blood 104: 92-99
7. Wu Q et al. (2020) Pentraxin 3: A promising therapeutic target for autoimmune diseases. Autoimmune Rev 19:102584.
8. Yu LM; et al. (2018) MicroRNA-224 inhibition prevents progression of cervical carcinoma by targeting PTX3. J Cell Biochem 119: 10278-10290