Pentraxins, humoral innate immunity and tissue injury

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Tissue damage elicits an inflammatory response, which comprises the rapid synthesis of acute phase molecules. The early local response shapes the resolution of inflammation. Pentraxins are evolutionary conserved soluble pattern recognition receptors, produced in the liver (e.g. C-reactive protein) or at sites of inflammation (the long pentraxin PTX3). Pentraxins behave as flexible adaptors of innate cell functions, complement activation and clearance of cell and matrix debris, regulating tissue hyperplasia and scarring and limiting the risk of autoimmunity associated to unscheduled cell death in vivo.

Introduction

Pentraxins are a superfamily of acute phase reactants characterized by a cyclic multimeric structure. The C-reactive protein (CRP) and serum amyloid P-component (SAP) are well-characterized short pentraxins. Hepatocytes produce human circulating CRP in response to pro-inflammatory mediators, most prominently IL-6; however, CRP synthesis and secretion in inflamed tissues also occurs [1, 2]. The concentration of human CRP, following an acute-phase signal, dramatically increases in the circulating blood; hepatic synthesis starts promptly, with blood concentrations rising already after about 6 hours and peaking around 48 hours. By contrast, the concentration of human (but not murine) SAP is relatively stable, even during the early acute-phase response. Short pentraxins are conserved during phylogenesis and no deficiency state of either CRP or SAP in humans has yet been reported. This possibly indicates that pentraxins confer a survival advantage; however, the mechanisms by which they act are not yet defined.

Pentraxin 3 (PTX3) is the prototypic long pentraxin, with a high degree of conservation from mouse to man. Both resident and innate immunity cells produce PTX3 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, Aspergillus fumigatus and influenza viruses in particular [3, 4]. PTX3 is endowed with activities unrelated to microorganisms. PTX3 associates to the extracellular matrix and protein tetramers are required for the assembly of the cumulus oophorus and female fertility [5]. Moreover, PTX3 interacts with other biologically active molecules, causing their functional blockade: this paradigm has been clearly demonstrated in the case of the fibroblast growth factor-2 (FGF-2), for which PTX3 behaves as an inhibitor [6, 7].

Short and long pentraxins recognize non-overlapping arrays of ligands [8]. The first fraction of the classical pathway of complement activation, C1q, represents the most notable exception. CRP and SAP bind to C1q. Similarly PTX3 binds to the globular head of C1q through the C-terminal pentraxin domain [9, 10].

Short pentraxins require a conformational change to bind to C1q and to activate complement. Chemical cross-linking artificially induces the configuration shift, possibly mimicking what happens in vivo when the protein is aggregated or bound to macromolecular templates [1, 2]. After cross-linking, short pentraxins reveal binding sites also for the fluid phase complement inhibitors, factor H and C4b-binding protein. The latter event is possibly involved in a negative feedback loop, which limits the inflammatory tissue damage [11]. By contrast, native PTX3 binds to C1q; the two molecules therefore interact in the fluid phase [9, 12]. Innate immune cells in inflamed tissues and fluids release C1q and PTX3, under the control of similar primary inflammatory stimuli such as TNFα and bacterial endotoxin. Interestingly, upon association with PTX3 in the fluid phase, the ability of C1q to activate the complement cascade [9] and to associate to apoptotic cell membranes [12] abates, possibly as the result of reciprocal steric hindrance.

The pentraxins CRP, SAP and PTX3 bind apoptotic cells and debris, and have long been associated with the response to tissue damage [1, 2]. Recognition of apoptotic cells is shared by other components of humoral innate immunity (e.g. collectins [13]) Here, we will discuss how pentraxins provide a paradigm for the function of humoral innate immunity in response to tissue injury and in editing self–non-self discrimination.

Section snippets

Tissue injury causes inflammation

Tissue injury is a critical initiator of the acute phase response. Platelets aggregate at the ends of injured vessels, converting fibrinogen to fibrin and preventing the loss of blood; neutrophils are attracted and activated, limiting the infection by bystander microorganisms; later on macrophages clear the injured site of all debris, including fibrin and dead parenchimal and inflammatory cells and orchestrate angiogenesis and tissue remodelling. Inflammation is dramatically important for

Tissue injury causes pentraxin production

Inflammatory cytokines trigger pentraxin generation. It is not therefore surprising that elevated levels of pentraxins are hallmarks of inflammatory disorders. Interestingly, in the phases of resolution, IL-10 and glucocorticoid hormones have been shown to costimulate PTX3 production induced by inflammatory signals, a likely scenario in the late phases of tissue damage ([27] and Andrea Doni and AM, unpublished data). Synoviocytes and synovial endothelial cells produce PTX3, which accumulates in

Pentraxins recognize apoptotic cells and debris

Pentraxins generated as a consequence of tissue damage specifically and often avidly recognize damaged cells and their constituents. Human CRP binds to the membranes of damaged cells, to various phospholipids, small nuclear ribonucleoprotein particles, and apoptotic cells [1, 45]. Human SAP binds in vivo to chromatin exposed by necrosis and to apoptotic cells; as a consequence, SAP displaces H1-core histones, solubilizing chromatin fragments otherwise quite insoluble (discussed in [46]). Human

Pentraxins shape the outcome of the acute tissue injury

PTX3 production could be an epiphenomenon, resulting from the generation of cytokines in injured tissues (and the IL-1receptor/MyD88 pathway is crucial for PTX3 generation [43••]). Alternatively, it may directly contribute to the extent and the outcome of the inflammatory response (Figure 2, panel b). A stringent genetic demonstration was obtained in ptx3-deficient mice, which have a response to ischemia similar to wild-type counterparts [43••]. However, they had an exacerbated damage after

Conclusions

Pentraxins are a key component of the humoral innate immune system [2]. In particular, because of the conservation in terms of structure and regulation, the long pentraxin PTX3 has provided unequivocal evidence for the role of the humoral arm of innate immunity in the response to pathogens and tissue damage [2, 3]. Pentraxins share with other fluid phase pattern recognition receptors the capacity to recognize apoptotic cells and debris. On the basis of available information, we surmise that, by

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) (to AAM, PR-Q, and AM), Telethon (to AM), Ministero Università e Ricerca (MUR, to AAM and to AM), Ministero della Salute – Alleanza Contro il Cancro, Progetto Finalizzato Oncologia (to AAM, PR-Q and to AM), European Union (Tolerage and Mugen projects, to AM), Fondazione CARIPLO (project Nobel, to AM).

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