Prototypic Long Pentraxin PTX3 Is Present in Breast Milk, Spreads in Tissues, and Protects Neonate Mice from Pseudomonas aeruginosa Lung Infection

Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b+ milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates’ health.

[1]  A. Mantovani,et al.  Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients , 2013, Innate immunity.

[2]  Ruth R. Montgomery,et al.  Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. , 2012, Immunity.

[3]  O. Levy,et al.  Neonatal Plasma Polarizes TLR4-Mediated Cytokine Responses towards Low IL-12p70 and High IL-10 Production via Distinct Factors , 2012, PloS one.

[4]  A. Larsson,et al.  Pentraxin 3 Values During Normal Pregnancy , 2011, Inflammation.

[5]  C. Garlanda,et al.  Pathogen Recognition by the Long Pentraxin PTX3 , 2011, Journal of biomedicine & biotechnology.

[6]  C. Garlanda,et al.  The Therapeutic Potential of the Humoral Pattern Recognition Molecule PTX3 in Chronic Lung Infection Caused by Pseudomonas aeruginosa , 2011, The Journal of Immunology.

[7]  K. Bremme,et al.  Cord blood monocyte subsets are similar to adult and show potent peptidoglycan‐stimulated cytokine responses , 2011, Immunology.

[8]  C. Garlanda,et al.  Role of complement and Fc{gamma} receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus. , 2010, Blood.

[9]  O. Levy,et al.  Role of innate host defenses in susceptibility to early-onset neonatal sepsis. , 2010, Clinics in perinatology.

[10]  M. Gobbi,et al.  Regulation of leukocyte recruitment by the long pentraxin PTX3 , 2010, Nature Immunology.

[11]  C. Garlanda,et al.  An integrated view of humoral innate immunity: pentraxins as a paradigm. , 2010, Annual review of immunology.

[12]  S. Self,et al.  Neonatal Innate TLR-Mediated Responses Are Distinct from Those of Adults1 , 2009, The Journal of Immunology.

[13]  M. Sperandio,et al.  Delayed but functional neutrophil extracellular trap formation in neonates. , 2009, Blood.

[14]  A. Weyrich,et al.  Comment on Chapter 5 , 1999 .

[15]  M. Triassi,et al.  Pseudomonas aeruginosa in a neonatal intensive care unit: molecular epidemiology and infection control measures , 2009, BMC infectious diseases.

[16]  H. Muller,et al.  Trans-Epithelial Immune Cell Transfer during Suckling Modulates Delayed-Type Hypersensitivity in Recipients as a Function of Gender , 2008, PloS one.

[17]  Y. Delneste,et al.  Pattern recognition receptors in the immune response against dying cells. , 2008, Current opinion in immunology.

[18]  A. Mantovani,et al.  Structural Characterization of PTX3 Disulfide Bond Network and Its Multimeric Status in Cumulus Matrix Organization* , 2008, Journal of Biological Chemistry.

[19]  A. Mantovani,et al.  Antiviral Activity of the Long Chain Pentraxin PTX3 against Influenza Viruses1 , 2008, The Journal of Immunology.

[20]  Yehuda Carmeli,et al.  Clinical and Economic Impact of Common Multidrug-Resistant Gram-Negative Bacilli , 2007, Antimicrobial Agents and Chemotherapy.

[21]  C. Garlanda,et al.  Complement Dependent Amplification of the Innate Response to a Cognate Microbial Ligand by the Long Pentraxin PTX31 , 2007, The Journal of Immunology.

[22]  Ofer Levy,et al.  Innate immunity of the newborn: basic mechanisms and clinical correlates , 2007, Nature Reviews Immunology.

[23]  C. Garlanda,et al.  The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps , 2007, The Journal of experimental medicine.

[24]  P. Allavena,et al.  Pentraxin 3 in plasma and vaginal fluid in women with preterm delivery * , 2007, BJOG : an international journal of obstetrics and gynaecology.

[25]  J. Klockgether,et al.  Sequence diversity of the mucABD locus in Pseudomonas aeruginosa isolates from patients with cystic fibrosis. , 2006, Microbiology.

[26]  O. Levy,et al.  The Adenosine System Selectively Inhibits TLR-Mediated TNF-α Production in the Human Newborn1 , 2006, The Journal of Immunology.

[27]  C. Garlanda,et al.  Elevated maternal levels of the long pentraxin 3 (PTX3) in preeclampsia and intrauterine growth restriction. , 2006, American journal of obstetrics and gynecology.

[28]  Michael Affolter,et al.  Modulation of Neonatal Microbial Recognition: TLR-Mediated Innate Immune Responses Are Specifically and Differentially Modulated by Human Milk1 , 2006, The Journal of Immunology.

[29]  B. Han,et al.  TNFα-Induced Long Pentraxin PTX3 Expression in Human Lung Epithelial Cells via JNK , 2005, The Journal of Immunology.

[30]  O. Levy,et al.  Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF-α Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-8481 , 2004, The Journal of Immunology.

[31]  A. Goldman,et al.  Breastfeeding: maintaining an irreplaceable immunological resource , 2004, Nature Reviews Immunology.

[32]  C. Van Lint,et al.  A Defect in Nucleosome Remodeling Prevents IL-12(p35) Gene Transcription in Neonatal Dendritic Cells , 2004, The Journal of experimental medicine.

[33]  C. Garlanda,et al.  PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization , 2004, Development.

[34]  A. Stadnyk,et al.  Role of MyD88 in Diminished Tumor Necrosis Factor Alpha Production by Newborn Mononuclear Cells in Response to Lipopolysaccharide , 2004, Infection and Immunity.

[35]  M. Grigorov,et al.  Soluble Forms of Toll-Like Receptor (TLR)2 Capable of Modulating TLR2 Signaling Are Present in Human Plasma and Breast Milk , 2003, The Journal of Immunology.

[36]  R. Zinkernagel On natural and artificial vaccinations. , 2003, Annual review of immunology.

[37]  O. Bezy,et al.  Characterization of the long pentraxin PTX3 as a TNFalpha-induced secreted protein of adipose cells. , 2003, Journal of lipid research.

[38]  Z. Bhutta,et al.  How many child deaths can we prevent this year? , 2003, The Lancet.

[39]  C. Garlanda,et al.  Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response , 2002, Nature.

[40]  R. Gibson,et al.  Cytokine Production by Human Milk Cells and Peripheral Blood Mononuclear Cells from the Same Mothers , 2002, Journal of Clinical Immunology.

[41]  V. Torri,et al.  Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients , 2001, Critical care medicine.

[42]  W. Shea-Eaton,et al.  Regulation of Milk Protein Gene Expression in Normal Mammary Epithelial Cells by Tumor Necrosis Factor. , 2001, Endocrinology.

[43]  M. Okabe,et al.  Two independent pathways of maternal cell transmission to offspring: through placenta during pregnancy and by breast‐feeding after birth , 2000, Immunology.

[44]  G Olivetti,et al.  PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. , 2000, Circulation.

[45]  M. Affolter,et al.  Innate Recognition of Bacteria in Human Milk Is Mediated by a Milk-Derived Highly Expressed Pattern Recognition Receptor, Soluble Cd14 , 2000, The Journal of experimental medicine.

[46]  O. Levy,et al.  Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein. , 1999 .

[47]  R. Gibson,et al.  Cytokines (IL-1β, IL-6, TNF-α, TGF-β1, and TGF-β2) and Prostaglandin E2 in Human Milk during the First Three Months Postpartum , 1999, Pediatric Research.

[48]  R. Garofalo,et al.  Expression of functional immunomodulatory and anti-inflammatory factors in human milk. , 1999, Clinics in perinatology.

[49]  Francesco Tedesco,et al.  Multimer Formation and Ligand Recognition by the Long Pentraxin PTX3 , 1997, The Journal of Biological Chemistry.

[50]  H. Tsutsumi,et al.  Enhanced cytokine production by milk macrophages following infection with respiratory syncytial virus , 1997, Journal of leukocyte biology.

[51]  H. Sengeløv,et al.  Granules and Secretory Vesicles in Human Neonatal Neutrophils , 1996, Pediatric Research.

[52]  T. Blundell,et al.  Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites. , 1996, Blood.

[53]  M. Sporn,et al.  Maternal rescue of transforming growth factor-beta 1 null mice. , 1994, Science.

[54]  S. Polberger,et al.  Macromolecular Absorption in Preterm and Term Infants , 1989, Acta paediatrica Scandinavica.

[55]  H. Pabst Effect of breast-feeding on immune response to BCG vaccination , 1989, The Lancet.

[56]  W. Müller,et al.  Cow milk protein antigens and antibodies in serum of premature infants during the first 10 days of life. , 1986, The Journal of pediatrics.

[57]  J. Schlesinger,et al.  EVIDENCE FOR TRANSMISSION OF LYMPHOCYTE RESPONSES TO TUBERCULIN BY BREAST-FEEDING , 1977, The Lancet.

[58]  A. Haddow,et al.  TREATMENT OF ENURESIS. , 1964, Lancet.

[59]  R. Lawrence,et al.  Human breast milk: current concepts of immunology and infectious diseases. , 2007, Current problems in pediatric and adolescent health care.

[60]  O. Levy,et al.  The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. , 2006, Journal of immunology.

[61]  W. Shea-Eaton,et al.  Regulation of milk protein gene expression in normal mammary epithelial cells by tumor necrosis factor. , 2001, Endocrinology.

[62]  R. Gibson,et al.  Cytokines (IL-1beta, IL-6, TNF-alpha, TGF-beta1, and TGF-beta2) and prostaglandin E2 in human milk during the first three months postpartum. , 1999, Pediatric research.