Pentraxins as a key component of innate immunity

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Pentraxins are a complex superfamily of multifunctional molecules characterized by a multimeric structure. C-reactive protein and pentraxin 3 (PTX3) are prototypic molecules of the short and long pentraxin family, respectively. PTX3 is conserved in evolution and produced by innate immune cells. Evidence suggests that PTX3 acts as a non-redundant component of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition, as well as a tuner of inflammation.

Introduction

Pentraxins are a superfamily of proteins that are highly conserved during evolution and characterized by a multimeric, usually pentameric structure [1, 2, 3••]. The classic short pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute-phase proteins in man and mouse, respectively. They are produced in the liver in response to inflammatory signals, most prominently IL-6. The prototypic long pentraxin 3 (PTX3) shares similarities with the classical short pentraxins; however, it has an unrelated long amino-terminal domain coupled to the carboxy-terminal pentraxin domain, and differs in gene organization, cellular source and ligands recognized [3••]. PTX3 is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, dendritic cells (DCs), fibroblasts and endothelial cells [3••, 4, 5, 6] in response to primary inflammatory signals (e.g. Toll-like receptor [TLR] engagement, TNF-α, IL-1β). PTX3 binds with high affinity the complement component C1q, the extracellular matrix component TNF-α-induced protein 6 (TNFAIP6; also called TNF-stimulated gene 6, TSG-6) and selected microorganisms, including Aspergillus fumigatus and Pseudomonas aeruginosa [7, 8, 9, 10, 11•]. PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs [3••, 8, 11•].

Recent studies in gene-modified mice have shown that PTX3 has complex non-redundant functions in vivo, ranging from the assembly of a hyaluronic acid-rich extracellular matrix and in vitro fertilization, to initiating innate immunity against diverse microorganisms [3••, 8, 10, 11•, 12, 13, 14]. Unlike the classic short pentraxins CRP and SAP, whose sequence and regulation have diverged between mouse and man, PTX3 is highly conserved in evolution. Thus, results obtained using genetic approaches in the mouse are likely to be informative for the function of PTX3 in man.

In this article we review recent progress made in defining the structure, immunobiology and in vivo role of PTX3. Evidence suggests that PTX3 is a key element of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition and activation.

Section snippets

Gene structure and regulation

The human PTX3 gene is organized in three exons coding for the leader peptide, the amino-terminal domain and the pentraxin domain of the protein. The PTX3 protein is 381 amino acids long, has a predicted molecular weight of 40 165 Da and consists of a carboxy-terminal 203 amino acid long pentraxin domain coupled with an amino-terminal 178 amino acid long domain unrelated to other known proteins. The PTX3 carboxy-terminal domain contains a canonical pentraxin signature and two conserved

Effector functions

The physiological functions attributed to PTX3 involve recognition and binding to different ligands including the complement component C1q [7, 9], the growth factor fibroblast growth factor 2 (FGF2) [33], the extracellular matrix protein TSG-6 [10] and the Omp A from Klebsiella pneumoniae (KpOmpA) [17•]. As with classical short pentraxins, PTX3 binds to plastic-immobilized C1q, inducing complement activation [7, 9]. By contrast, fluid-phase binding of PTX3 to C1q inhibits complement activation

Role in innate resistance and inflammation

Studies in PTX3-deficient mice suggest that the role played by PTX3 in innate resistance is non-redundant and relevant in selected fungal and bacterial infections (A. fumigatus, P. aeruginosa, Salmonella typhimurium) and irrelevant in others (Listeria monocytogenes, Staphylococcus aureus, polymicrobic intra-abdominal sepsis; C Garlanda, unpublished; [8]). These results suggest that PTX3 deficiency does not cause a generalized impairment of host resistance to microbial pathogens, and that PTX3

Pathogen versus apoptotic self recognition

Similar to other members of the pentraxin family [49, 50], PTX3 binds apoptotic cells, thereby inhibiting their recognition by DCs [51]. Binding occurs late in the apoptotic process and enhances cytokine production by DCs. In addition, preincubation of apoptotic cells with PTX3 enhances C1q binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells.

Myeloid, but not plasmacytoid, DCs are major producers of PTX3 in response to

Conclusions

CRP was the first innate immune molecule capable of recognizing microbial moieties to be identified [3••]. Yet, in spite of its widespread use as a diagnostic tool in the clinic, its in vivo function has not been unequivocally defined. Indeed, the considerable differences in sequence and, most prominently, regulation (CRP is not an acute phase protein in mouse) have precluded the use of straightforward genetic approaches to explore its in vivo function [36••]. By contrast, gene targeting of the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Telethon, Ministero Istruzione Università e Ricerca (MIUR), Ministero della Salute, Consiglio Nazionale delle Ricerche (CNR), European Commission. We wish to thank Felice De Ceglie for his invaluable help in the preparation of Figure 1, and L Romani for illuminating discussions.

References (52)

  • M. Klouche et al.

    Human herpesvirus 8-derived viral IL-6 induces PTX3 expression in Kaposi's sarcoma cells

    AIDS

    (2002)
  • R. Lang et al.

    Shaping gene expression in activated and resting primary macrophages by IL-10

    J Immunol

    (2002)
  • A.J. Nauta et al.

    Recognition and clearance of apoptotic cells: a role for complement and pentraxins

    Trends Immunol

    (2003)
  • R. Gaziano et al.

    Combination therapy with pentraxin 3 and antifungals in experimental aspergillosis

    Antimicrob Agents Chemother

    (2004)
  • A. Familian et al.

    Chromatin-independent binding of serum amyloid P component to apoptotic cells

    J Immunol

    (2001)
  • C. Garlanda et al.

    Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility

    Annu Rev Immunol

    (2005)
  • A. Doni et al.

    Production of the soluble pattern recognition receptor PTX3 by myeloid, but not plasmacytoid, dendritic cells

    Eur J Immunol

    (2003)
  • G.W. Lee et al.

    TSG-14, a tumor necrosis factor- and IL-1-inducible protein, is a novel member of the pentaxin family of acute phase proteins

    J Immunol

    (1993)
  • A.J. Nauta et al.

    Human renal epithelial cells produce the long pentraxin PTX3

    Kidney Int

    (2005)
  • A.J. Nauta et al.

    Biochemical and functional characterization of the interaction between pentraxin 3 and C1q

    Eur J Immunol

    (2003)
  • A. Salustri et al.

    PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization

    Development

    (2004)
  • S.N. Diniz et al.

    PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages

    J Leukoc Biol

    (2004)
  • S. Varani et al.

    Knockout of pentraxin 3, a downstream target of growth differentiation factor-9, causes female subfertility

    Mol Endocrinol

    (2002)
  • D.G. Souza et al.

    Increased mortality and inflammation in tumor necrosis factor-stimulated gene-14 transgenic mice after ischemia and reperfusion injury

    Am J Pathol

    (2002)
  • A.A. Dias et al.

    TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis

    J Leukoc Biol

    (2001)
  • F. Breviario et al.

    Interleukin-1-inducible genes in endothelial cells. Cloning of a new gene related to C-reactive protein and serum amyloid P component

    J Biol Chem

    (1992)

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