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Chapter 10 : Phagocytes Are a Source of the Fluid-Phase Pattern Recognition Receptor PTX3: Interplay between Cellular and Humoral Innate Immunity
Category: Microbial Genetics and Molecular Biology; Bacterial Pathogenesis
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This chapter reviews how phagocytes represent a key source of the fluid-phase pattern recognition receptor (PRR) and how this molecule is essential for innate resistance against diverse pathogens. Mononuclear phagocytes and myeloid-derived dendritic cells (DCs) are a major source of the long pentraxin PTX3. Western blot and immunofluorescence analysis indicate that PTX3 is associated with the extracellular matrix of the cumulus oophorus. Recent analysis of PTX3 gene regulation has yielded unexpected results. While PTX3 promotes removal of selected pathogens by professional phagocytes, it inhibits removal of apoptotic cells. The major integral component of cumulus matrix is hyaluronan, a large glycosaminoglycan responsible for the viscoelastic properties of this matrix. Different gene expression studies indicated that PTX3 is one of the most upregulated genes related to inflammation and angiogenesis induced during implantation. PTX3 behaves as an acute-phase response protein since its blood levels can increase up to 1,000-fold depending on the severity of inflammation. Recent results show that pregnancy itself, a condition associated with relevant involvement of inflammatory molecules at the implantation site, is associated with a slight increase in maternal circulating PTX3 levels compared with the nonpregnant condition. Neutrophils serve as a reservoir, ready for rapid release, of a key component of humoral innate immunity, and complement its subsequent delayed neosynthesis by macrophages and DCs.
Structure of PTX3 protomer with its N- and C-terminal domains, the leader peptide, and the pentraxin signature. Cysteine residues relevant for interchain disulfide bonds and the N-linked glycosylation site at aspartic acid residue 220 are shown.
Pentraxins in innate immunity: liver-derived short pentraxins (e.g., CRP and SAP) and tissue-expressed long pentraxins (e.g., PTX3) are produced in response to microbial sensing and inflammatory cytokines and are likely to fulfill complementary functions in innate resistance to pathogens, tuning of inflammation, editing self/nonself discrimination, and participating in extracellular matrix architecture and female fertility (adapted with permission from Bottazzi et al., 2006 ).
Ligands recognized by PTX3 and short pentraxins