PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer.

PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.

The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection.

Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs.

Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation.

BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).

Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both.

BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.

Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection.

BACKGROUND: Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. METHODS: We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. RESULTS: We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. CONCLUSIONS: These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity.

AIMS: Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity. METHODS AND RESULTS: PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers. CONCLUSION: Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.

Atorvastatin reduces long pentraxin 3 expression in vascular cells by inhibiting protein geranylgeranylation.

BACKGROUND: The long pentraxin PTX3 is an acute-phase multi-functional protein that might play both positive and detrimental effects under different pathophysiological conditions. We previously showed that statins down-regulate the release of PTX3 in human endothelial cells (ECs). The present study investigated the mechanism mediating this effect, its occurrence in other cells involved in atherogenesis, and whether it takes place in experimental atherosclerosis. METHODS AND RESULTS: We found that atorvastatin (1-5 µmol/L) decreased the production and release of PTX3 in human ECs through a post-transcriptional effect. Co-incubation with mevalonate or geranylgeranyl pyrophosphate prevented this effect. Direct blockade of geranylgeranyl transferase I by GGTI-286, treatment with the Rac inhibitor NSC23766 or silencing of the geranylgeranylated GTPase Rac2 by siRNA closely mimicked the action of atorvastatin. In contrast, inactivation of other geranylgeranylated proteins such as RhoA, RhoB, and RhoC or Rac1 did not affect PTX3 release. In addition, we found that atorvastatin also decreased PTX3 secretion in aortic SMCs through a mechanism likely dependent on protein geranylgeranylation, while no effect was observed in monocytes. Finally, we found that atherosclerotic lesions from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) showed less immunoreactive PTX3 than lesions from control animals. CONCLUSIONS: Results suggest that statins may interfere with PTX3 expression in vascular cells via inhibition of protein geranylgeranylation. Since PTX3 is increasingly regarded as an important mediator of the inflammatory response underlying atherosclerosis and its complications, these results highlight the need for further studies of the role of PTX3 and its potential pharmacological modulation in cardiovascular disease.

The long pentraxin PTX3 as a correlate of cancer-related inflammation and prognosis of malignancy in gliomas.

Inflammation is a component of glioma microenvironment. PTX3 is a component of the humoral arm of innate immunity and a candidate marker of inflammation. In the present study we assessed the expression of PTX3 in gliomas by immunohistochemistry. PTX3 expression differed across low and high-grade tumors based on histopathological diagnosis and clinical severity, positively correlating with tumor grade and severity. In a multivariate logistic regression model, only the PTX3 score was significantly associated with the presence of a high-grade tumor. Thus, PTX3 may represent a new marker of cancer-related inflammation and glioma malignancy.

The "sweet" side of a long pentraxin: how glycosylation affects PTX3 functions in innate immunity and inflammation.

Innate immunity represents the first line of defense against pathogens and plays key roles in activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules (PRMs) that recognize pathogen-associated molecular patterns and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. The long pentraxin PTX3 is a prototypic soluble PRM that is produced at sites of infection and inflammation by both somatic and immune cells. Gene targeting of this evolutionarily conserved protein has revealed a non-redundant role in resistance to selected pathogens. Moreover, PTX3 exerts important functions at the crossroad between innate immunity, inflammation, and female fertility. The human PTX3 protein contains a single N-glycosylation site that is fully occupied by complex type oligosaccharides, mainly fucosylated and sialylated biantennary glycans. Glycosylation has been implicated in a number of PTX3 activities, including neutralization of influenza viruses, modulation of the complement system, and attenuation of leukocyte recruitment. Therefore, this post translational modification might act as a fine tuner of PTX3 functions in native immunity and inflammation. Here we review the studies on PTX3, with emphasis on the glycan-dependent mechanisms underlying pathogen recognition and crosstalk with other components of the innate immune system.

TIR8/SIGIRR is an Interleukin-1 Receptor/Toll Like Receptor Family Member with Regulatory Functions in Inflammation and Immunity.

Interleukin-1R like receptors (ILRs) and Toll Like Receptors (TLRs) are key receptors of innate immunity, inflammation, and orientation of the adaptive response. They belong to a superfamily characterized by the presence of a conserved intracellular domain, the Toll/IL-1R (TIR) domain, which is involved in the activation of a signaling cascade leading to activation of transcription factors associated to inflammation. The activation of inflammatory responses and immunity by ILRs or TLRs signaling is potentially detrimental for the host in acute and chronic conditions and is tightly regulated at different levels by receptor antagonists, decoy receptors or signaling molecules, and miRNAs. Recent evidence suggests that the ILRs family member TIR8 (also known as SIGIRR) is a regulatory protein acting intracellularly to inhibit ILRs and TLRs signaling. In particular, current evidence suggests that TIR8/SIGIRR dampens TLRs-mediated activation and inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33), and Th17 (IL-1) differentiation. Studies with Tir8/Sigirr-deficient mice showed that the ability to dampen signaling from ILRs and TLRs family members makes TIR8/SIGIRR a key regulator of inflammation. Here, we summarize our current understanding of the structure and function of TIR8/SIGIRR, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation.

Influence of pentraxin 3 (PTX3) genetic variants on myocardial infarction risk and PTX3 plasma levels.

PTX3 is a long pentraxin of the innate immune system produced by different cell types (mononuclear phagocytes, dendritic cells, fibroblasts and endothelial cells) at the inflammatory site. It appears to have a cardiovascular protective function by acting on the immune-inflammatory balance in the cardiovascular system. PTX3 plasma concentration is an independent predictor of mortality in patients with acute myocardial infarction (AMI) but the influence of PTX3 genetic variants on PTX3 plasma concentration has been investigated very little and there is no information on the association between PTX3 variations and AMI. Subjects of European origin (3245, 1751 AMI survivors and 1494 controls) were genotyped for three common PTX3 polymorphisms (SNPs) (rs2305619, rs3816527, rs1840680). Genotype and allele frequencies of the three SNPs and the haplotype frequencies were compared for the two groups. None of the genotypes, alleles or haplotypes were significantly associated with the risk of AMI. However, analysis adjusted for age and sex indicated that the three PTX3 SNPs and the corresponding haplotypes were significantly associated with different PTX3 plasma levels. There was also a significant association between PTX3 plasma concentrations and the risk of all-cause mortality at three years in AMI patients (OR 1.10, 95% CI: 1.01-1.20, p = 0.02). Our study showed that PTX3 plasma levels are influenced by three PTX3 polymorphisms. Genetically determined high PTX3 levels do not influence the risk of AMI, suggesting that the PTX3 concentration itself is unlikely to be even a modest causal factor for AMI. Analysis also confirmed that PTX3 is a prognostic marker after AMI.