The soluble pattern recognition receptor pentraxin-3 in innate immunity, inflammation and fertility

doi:10.1016/j.jri.2009.05.006

Journal of Reproductive Immunology

Volume 83, Issues 1–2, December 2009, Pages 128-133

https://doi.org/10.1016/j.jri.2009.05.006 Get rights and content

Abstract

The innate immune system consists of a cellular and a humoral arm. Components of humoral immunity include diverse molecular families, which represent functional ancestors of antibodies. They play key roles as effectors and modulators of innate resistance and inflammation. The long pentraxin PTX3 represents a prototype humoral effector molecule. Gene targeting of this evolutionarily conserved long pentraxin has unequivocally defined its role at the crossroads of innate immunity, inflammation, matrix deposition and female fertility. Here, we will review the studies on PTX3, which emphasize its role as a multifunctional soluble pattern recognition receptor acting as a non-redundant component of the humoral arm of innate immunity involved in fine-tuning inflammation, matrix deposition, angiogenesis and, in particular, in female 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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Cited by (39)

Long-chain pentraxin 3 possesses agglutination activity and plays a role in host defense against bacterial infection in Oreochromis niloticus
2023, Developmental and Comparative Immunology
Pentraxin 3 (PTX3) is a soluble pattern recognition molecule in the innate immune system that has multiple functions. It is involved in resisting pathogen infection. However, the functions of PTX3 in teleost fish are not well understood. In this study, we identified and characterized PTX3 in Nile tilapia (Oreochromis niloticus) (OnPTX3). The open reading frame of OnPTX3 was found to be 1305 bp, encoding 434 aa. We conducted spatial mRNA expression analysis and found that the expression of OnPTX3 was significantly increased after infection with Streptococcus agalactiae and Aeromonas hydrophila, both in vivo and in vitro. We also observed that recombinant OnPTX3 protein could bind and agglutinate bacterial pathogen. Furthermore, OnPTX3 enhanced the phagocytosis of bacteria (S. agalactiae and A. hydrophila) by head kidney macrophages. Additionally, OnPTX3 was found to influence the expression of inflammatory cytokines, suggesting its involvement in the regulation of the inflammatory response. Moreover, OnPTX3 was shown to promote complement-mediated hemolysis and possess antibacterial activity. In conclusion, our research demonstrates that OnPTX3 has bacterial binding and agglutination activities, enhances phagocytosis, and regulates inflammation. It plays a crucial role in the defense of Nile tilapia against pathogenic bacteria, providing valuable insights for the prevention and control of aquatic diseases in the future.
LncRNA MEG3 alleviates PFOS induced placental cell growth inhibition through its derived miR-770 targeting PTX3
2022, Environmental Pollution
Citation Excerpt :
PTX3 belongs to the long pentraxin subfamily, and is evolutionarily conserved in the innate immune system (Doni et al., 2016). PTX3 is a key regulator in the cellular response to inflammatory stress, which has been closely linked to development of inflammation, fertility and autoimmune disorders (Garlanda et al., 2009). Increased level of PTX3 was found in pregnant women who developed preeclampsia (Hamad et al., 2012a), and PTX3 expression was dramatically increased in placenta from unexplained recurrent pregnancy loss (URPL) (Zeybek et al., 2019a).
Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10⁻¹, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.
Estimation of asymmetric dimethylarginine (ADMA), placental growth factor (PLGF) and pentraxin 3 (PTX 3) in women with preeclampsia
2018, Pregnancy Hypertension
To evaluate the sequential trend of asymmetric dimethylarginine (ADMA), placental growth factor (PLGF) and pentraxin 3 (PTX 3) in pregnancies developing preeclampsia (PE) as compared to healthy pregnancy (HP) and to estimate their predictive value for development of PE later in pregnancy.
Nested case control design, sampling was done in 13 women with PE and 21 age matched healthy pregnant women at 11–13 weeks, 20–22 weeks and 30–32 weeks of gestation.
PLGF, ADMA, and PTX 3 were estimated temporally.
Serum ADMA and PTX 3 levels were higher in PE than HP even at 11–13 weeks and remained elevated throughout the gestation. PTX 3 concentration increased in both the groups with advancing gestation however significant rise was observed only in HP group. PLGF levels also increased with advancing gestation in HP group while in PE, there was a rise till 20–22 weeks of gestation followed by fall at 30–32 weeks. PLGF levels were lower in PE at 30–32 weeks than healthy pregnancy. Area under curve (AUC) for ADMA and PTX 3 were: at 11–13 weeks; 95.95% and 83.33% and 20–22 weeks; 89.88% and 90.06% respectively. At 30–32 weeks, PLGF and ADMA demonstrated an AUC of 86.51% and 86.51% respectively.
Abnormally elevated ADMA and PTX 3 levels precede the manifestation of PE and suggest endothelial dysfunction with exaggerated inflammatory response in PE. Both ADMA and PTX 3 can be used to segregate high risk women for development of PE than others in early pregnancy.
Neuroinflammation in Alzheimer's disease: Pleiotropic roles for cytokines and neuronal pentraxins
2018, Behavioural Brain Research
Neuroinflammation is a potential factor speculated to underlie Alzheimer’s disease (AD) etiopathogenesis and progression. The overwhelming focus in this area of research to date has been on the chronic upregulation of pro-inflammatory cytokines to understand how neuroinflammatory mechanisms contribute to neurodegeneration. Yet, it is important to understand the pleiotropic roles of these cytokines in modulating neuroinflammation in which they cannot be labeled as a strictly “good” or “bad” biomarker phenotype. As such, biomarkers with more precise functions are needed to better understand how neuroinflammation impacts the brain in AD. Neuronal pentraxins are a concentration- dependent group of pro- or anti- inflammatory cytokines. There is contradictory evidence of these pentraxins as being both neuroprotective and potentially detrimental in AD. Potential neuroprotective examples include their ability to predict AD-related outcomes such as cognition, memory function and synaptic refinement. This review will briefly outline the basis of AD and subsequently summarize findings for neuropathological mechanisms of neuroinflammation, roles for traditional pro-and anti-inflammatory cytokines, and data found thus far on the neuronal pentraxins.
The relationship of pentraxin-3 levels with IL-17, fetuin-A, insulin in patients with Behçet's disease
2017, Dermatologica Sinica
Pentraxin (PTX) 3 is synthesized by leukocytes, dendritic cells, endothelial cells and monocytes in response to IL-1 and tumor necrosis factor (TNF)-α, and it might be informative regarding local inflammation. In additionally, pentraxin (PTX)-3, produced by endothelial cells in atherosclerotic plaques, acts as a modulator of inflammatory processes and is involved in the development of atherosclerotic lesions.
This study aimed to identify the levels of proteins, such as PTX and fetuin-A, which are thought to play a role in the progression of atherosclerotic and cardiovascular disorders in patients with BD, and to investigate the relationship of these protein levels with BD activity, inflammatory cytokines, insulin resistance and dyslipidaemia.
This study included 58 patients (36 females, 22 males) with BD and 20 healthy controls. Serum PTX-3, fetuin-A, interleukin (IL)-17 and insulin concentrations were determined. Homeostasis model of insulin resistance (HOMA-IR) values were calculated, and disease activity was assessed using BD Current Activity Form (BDCAF) scores.
The levels pentraxin-3, fetuin-A, IL-17, insulin and HOMA-IR in patients with BD were found to be higher than control subjects (p < 0.05). PTX-3 and fetuin-A levels showed no correlation with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or scores on the various BDCAF domains. IL-17 levels were significantly positively correlated with the BDCAF arthritis score. No significant relationships were identified between the lipid profile and PTX-3, IL-17 or fetuin-A levels. No correlations were found among PTX, IL-17, fetuin-A, and insulin and HOMA-IR levels (p > 0.05).
Similar to CRP, PTX-3 is an acute-phase reactant that is considered an inflammatory and atherosclerotic biomarker. This study showed that PTX-3 levels can increase, similar to IL-17, but no relationship was detected between disease activity and coronary risk factors such as serum lipids, glucose intolerance and obesity. This was a cross-sectional study; therefore, the patients should be followed in long-term studies to determine whether higher PTX levels in BD patients are associated with a higher incidence of cardiovascular disease.
Serum pentraxin 3 levels are negatively associated with carotid intima media thickness in non-obese rheumatoid arthritis patients
2016, International Journal of Cardiology
Citation 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].
Pentraxin-3 (PTX3) is a long pentraxin that is supposed to participate in the inflammatory process and in atherosclerosis.
To study PTX3 serum levels in rheumatoid arthritis (RA) patients to know if its serum levels may reflect disease activity and/or subclinical atherosclerosis.
PTX3 and carotid intima media thickness (IMT) were studied in 85 RA patients (83.5% females, median age of 59 years old, median disease duration of 13 years) along with its demographic, clinical, serological and lipid profile. For comparison PTX3 was measured in 85 healthy volunteers.
PTX3 levels in RA patients were similar to controls (p = 0.21) and did not correlate with inflammatory activity measured by ESR (p = 0.39) CRP (p = 0.18) and DAS28 (p = 0.67). Serum PTX3 levels were higher in nonobese RA patients than in obese (BMI vs PTX3 with rho = − 0.27; 95%IC = − 0.46 to − 0.06; p = 0.009). In non-obese patients, PTX3 correlated negatively with carotid IMT (rho = − 0.40; 95%IC = − 0.66 to − 0.06; p = 0.01) but not in the obese ones (p = 0.26). In the obese RA patients there was a negative correlation between PTX3 levels and LDL/HDL ratio (Rho = − 0.29; 95%IC = − 0.53–0.01; p = 0.03).
PTX3 levels do not reflect inflammatory process in RA. However, it exerts a protective role in the process of atherogenesis in non-obese RA patients.

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The soluble pattern recognition receptor pentraxin-3 in innate immunity, inflammation and fertility

Abstract

Introduction

Section snippets

The long pentraxin PTX3

Role of PTX3 in innate immunity and inflammation

Role in self/non-self discrimination

Role in angiogenesis

Role of PTX3 in female fertility

PTX3 as a marker in human pathology

Concluding remarks

Acknowledgment

J. Biol. Chem.

Curr. Opin. Immunol.

Blood

Am. J. Obstet. Gynecol.

J. Biol. Chem.

Placenta

Mol. Immunol.

Immunity

Curr. Opin. Immunol.

Am. J. Obstet. Gynecol.

J. Biol. Chem.

Trends Immunol.

J. Biol. Chem.

Fertil. Steril.

Pentraxin 3 in plasma and vaginal fluid in women with preterm delivery

BJOG

Neutrophil extracellular traps kill bacteria

Science

Complement dependent amplification of the innate response to a cognate microbial ligand by the long pentraxin PTX3

J. Immunol.

Binding of the long pentraxin PTX3 to Factor H: interacting domains and function in the regulation of complement activation

J. Immunol.

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

Eur. J. Immunol.