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Article: Preventing Peritoneal Dialysis-Associated Fibrosis by Therapeutic Blunting of Peritoneal Toll-Like Receptor Activity.

Raby, Anne-Catherine / Labéta, Mario O

2018 Volume 9, Page(s) 1692

Abstract: Peritoneal dialysis (PD) is an essential daily life-saving treatment for end-stage renal failure. PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure as a result of progressive fibrosis. Peritoneal infections, ... ...

Abstract	Peritoneal dialysis (PD) is an essential daily life-saving treatment for end-stage renal failure. PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure as a result of progressive fibrosis. Peritoneal infections, with the concomitant acute inflammatory response and membrane fibrosis development, worsen PD patient outcomes. Patients who remain infection-free, however, also show evidence of inflammation-induced membrane damage and fibrosis, leading to PD cessation. In this case, uraemia, prolonged exposure to bio-incompatible PD solutions and surgical catheter insertion have been reported to induce sterile peritoneal inflammation and fibrosis as a result of cellular stress or tissue injury. Attempts to reduce inflammation (either infection-induced or sterile) and, thus, minimize fibrosis development in PD have been hampered because the immunological mechanisms underlying this PD-associated pathology remain to be fully defined. Toll-like receptors (TLRs) are central to mediating inflammatory responses by recognizing a wide variety of microorganisms and endogenous components released following cellular stress or generated as a consequence of extracellular matrix degradation during tissue injury. Given the close link between inflammation and fibrosis, recent investigations have evaluated the role that TLRs play in infection-induced and sterile peritoneal fibrosis development during PD. Here, we review the findings and discuss the potential of reducing peritoneal TLR activity by using a TLR inhibitor, soluble TLR2, as a therapeutic strategy to prevent PD-associated peritoneal fibrosis.
Language	English
Publishing date	2018-11-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2018.01692
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Therapeutic Boosting of the Immune Response: Turning to CD14 for Help.

Raby, Anne-Catherine / Labéta, Mario O

Current pharmaceutical biotechnology

2016 Volume 17, Issue 5, Page(s) 414–418

Abstract: The Toll-like family of immune receptors (TLRs) are critical for an efficient immune response to a variety of microorganisms and other antigens that may cause pathology. Modulating immune responses by targeting TLRs therefore has substantial therapeutic ... ...

Abstract	The Toll-like family of immune receptors (TLRs) are critical for an efficient immune response to a variety of microorganisms and other antigens that may cause pathology. Modulating immune responses by targeting TLRs therefore has substantial therapeutic potential, and a number of TLR-based therapeutic strategies have been developed. Minimizing the adverse effects that may result from the therapeutic manipulation of these signalling receptors nevertheless remains a major challenge. Efficient responses via TLRs require the activity of the co-receptor CD14, which enhances TLR responses. In an attempt to boost the immune response for therapeutic purposes, we have sought to target CD14 to achieve TLR modulation. Here we discuss the design, activity and therapeutic development options of TLR-derived peptides that interact with CD14 and enhance its co-receptor activity, thus amplifying TLR-mediated responses. This strategy represents a promising alternative to current TLR-based therapies, as it has the potential to amplify responses to different pathogens mediated by different TLRs by targeting the common TLR co-receptor, CD14.
MeSH term(s)	Animals ; Histocompatibility Antigens Class II/immunology ; Humans ; Lipopolysaccharide Receptors/immunology ; Peptides/immunology ; Signal Transduction ; Toll-Like Receptors/immunology ; Vaccines/immunology
Chemical Substances	Histocompatibility Antigens Class II ; Lipopolysaccharide Receptors ; Peptides ; Toll-Like Receptors ; Vaccines
Language	English
Publishing date	2016-01-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2132197-8
ISSN	1873-4316 ; 1389-2010
ISSN (online)	1873-4316
ISSN	1389-2010
DOI	10.2174/1389201017666160114095708
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Article ; Online: Calprotectin blockade inhibits long-term vascular pathology following peritoneal dialysis-associated bacterial infection.

Cetin, Esra / Mazzarino, Morgane / González-Mateo, Guadalupe T / Kopytina, Valeria / Meran, Soma / Fraser, Donald / López-Cabrera, Manuel / Labéta, Mario O / Raby, Anne-Catherine

Frontiers in cellular and infection microbiology

2023 Volume 13, Page(s) 1285193

Abstract: Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases ... ...

Abstract	Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases late CV mortality risk. However, the underlying mechanism(s) remains to be elucidated before safe and efficient anti-inflammatory interventions can be developed. Damage-Associated Molecular Patterns (DAMPs) have been shown to contribute to the acute inflammatory response to infections, but a potential role for DAMPs in mediating long-term vascular inflammation and CV risk following infection resolution in PD, has not been investigated. We found that bacterial peritonitis in mice that resolved within 24h led to CV disease-promoting systemic and vascular immune-mediated inflammatory responses that were maintained up to 28 days. These included higher blood proportions of inflammatory leukocytes displaying increased adhesion molecule expression, higher plasma cytokines levels, and increased aortic inflammatory and atherosclerosis-associated gene expression. These effects were also observed in infected nephropathic mice and amplified in mice routinely exposed to PD fluids. A peritonitis episode resulted in elevated plasma levels of the DAMP Calprotectin, both in PD patients and mice, here the increase was maintained up to 28 days.
MeSH term(s)	Humans ; Mice ; Animals ; Peritoneal Dialysis/adverse effects ; Peritoneal Dialysis/methods ; Peritonitis ; Inflammation/complications ; Bacterial Infections/complications ; Atherosclerosis/complications
Language	English
Publishing date	2023-11-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2023.1285193
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Article ; Online: Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology.

Mazzarino, Morgane / Cetin, Esra / Bartosova, Maria / Marinovic, Iva / Ipseiz, Natacha / Hughes, Timothy R / Schmitt, Claus Peter / Ramji, Dipak P / Labéta, Mario O / Raby, Anne-Catherine

Frontiers in immunology

2023 Volume 14, Page(s) 1240679

Abstract: Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR ... ...

Abstract	Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients' plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients' plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.
MeSH term(s)	Humans ; Animals ; Mice ; Renal Insufficiency, Chronic/pathology ; Alarmins ; Atherosclerosis/drug therapy ; Inflammation/metabolism ; Cardiovascular Diseases/complications ; Leukocyte L1 Antigen Complex
Chemical Substances	Alarmins ; Leukocyte L1 Antigen Complex
Language	English
Publishing date	2023-10-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1240679
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Article ; Online: Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution-induced fibrosis.

Raby, Anne-Catherine / González-Mateo, Guadalupe T / Williams, Aled / Topley, Nicholas / Fraser, Donald / López-Cabrera, Manuel / Labéta, Mario O

Kidney international

2018 Volume 94, Issue 2, Page(s) 346–362

Abstract: Peritoneal membrane failure due to fibrosis limits the use of peritoneal dialysis (PD). Peritoneal fibrosis may potentially be induced by sterile inflammation caused by ongoing cellular stress due to prolonged exposure to PD solutions (PDS). Effective ... ...

Abstract	Peritoneal membrane failure due to fibrosis limits the use of peritoneal dialysis (PD). Peritoneal fibrosis may potentially be induced by sterile inflammation caused by ongoing cellular stress due to prolonged exposure to PD solutions (PDS). Effective therapies to prevent this process remain to be developed. Toll-like receptors (TLRs) mediate sterile inflammation by recognizing damage-associated molecular patterns (DAMPs) released by cellular stress. We evaluated the involvement of TLRs and DAMPs in PDS-induced fibrosis models and the therapeutic potential of TLR-DAMP targeting for preventing fibrosis. A range of PDS elicited pro-inflammatory and fibrotic responses from PD patient peritoneal leukocytes, mesothelial cells and mouse peritoneal leukocytes. TLR2/4 blockade of human peritoneal cells or TLR2/4 knockouts inhibited these effects. PDS did not induce rapid ERK phosphorylation or IκB-α degradation, suggesting that they do not contain components capable of direct TLR activation. However, PDS increased the release of Hsp70 and hyaluronan, both TLR2/4 DAMP ligands, by human and mouse peritoneal cells, and their blockade decreased PDS-driven inflammation. Soluble TLR2, a TLR inhibitor, reduced PDS-induced pro-inflammatory and fibrotic cytokine release ex vivo. Daily catheter infusion of PDS in mice caused peritoneal fibrosis, but co-administration of soluble TLR2 prevented fibrosis, suppressed pro-fibrotic gene expression and pro-inflammatory cytokine production, reduced leukocyte/neutrophil recruitment, recovered Treg cell levels and increased the Treg:Th17 ratio. Thus, TLR2/4, Hsp70 and hyaluronan showed major roles in PDS-induced peritoneal inflammation and fibrosis. The study demonstrates the therapeutic potential of a TLR-DAMP targeting strategy to prevent PDS-induced fibrosis.
MeSH term(s)	Alarmins/antagonists & inhibitors ; Alarmins/immunology ; Alarmins/metabolism ; Animals ; Cells, Cultured ; Cytokines/immunology ; Cytokines/metabolism ; Dialysis Solutions/toxicity ; Epithelial Cells/immunology ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; Healthy Volunteers ; Humans ; Inflammation/chemically induced ; Inflammation/immunology ; Inflammation/pathology ; Inflammation/prevention & control ; Kidney Failure, Chronic/therapy ; Lymphocytes ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Peritoneal Dialysis/adverse effects ; Peritoneal Dialysis/methods ; Peritoneal Fibrosis/chemically induced ; Peritoneal Fibrosis/immunology ; Peritoneal Fibrosis/pathology ; Peritoneal Fibrosis/prevention & control ; Peritoneum/cytology ; Peritoneum/pathology ; Primary Cell Culture ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/metabolism ; Toll-Like Receptor 2/administration & dosage ; Toll-Like Receptor 2/metabolism ; Toll-Like Receptors/antagonists & inhibitors ; Toll-Like Receptors/genetics ; Toll-Like Receptors/metabolism
Chemical Substances	Alarmins ; Cytokines ; Dialysis Solutions ; Recombinant Proteins ; TLR2 protein, human ; Toll-Like Receptor 2 ; Toll-Like Receptors
Language	English
Publishing date	2018-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2018.03.014
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Article: Soluble Toll-like receptor 2 is a biomarker for sepsis in critically ill patients with multi-organ failure within 12 h of ICU admission.

Holst, Benjamin / Szakmany, Tamas / Raby, Anne-Catherine / Hamlyn, Vincent / Durno, Kimberley / Hall, Judith E / Labéta, Mario O

Intensive care medicine experimental

2017 Volume 5, Issue 1, Page(s) 2

Abstract: Soluble TLR2 levels are elevated in infective and inflammatory conditions, but its diagnostic value with sepsis-induced multi-organ failure has not been evaluated. 37 patients with a diagnosis of severe sepsis/septic shock (sepsis) and 27 patients with ... ...

Abstract	Soluble TLR2 levels are elevated in infective and inflammatory conditions, but its diagnostic value with sepsis-induced multi-organ failure has not been evaluated. 37 patients with a diagnosis of severe sepsis/septic shock (sepsis) and 27 patients with organ failure without infection (SIRS) were studied. Median (IQR) plasma sTLR2 levels were 2.7 ng/ml (1.4-6.1) in sepsis and 0.6 ng/ml (0.4-0.9) in SIRS p < 0.001. sTLR2 showed good diagnostic value for sepsis at cut-off of 1.0 ng/ml, AUC:0.959. We report the ability of sTLR2 levels to discriminate between sepsis and SIRS within 12 h of ICU admission in patients with multi-organ failure.
Language	English
Publishing date	2017-01-13
Publishing country	Germany
Document type	Letter
ZDB-ID	2740385-3
ISSN	2197-425X
ISSN	2197-425X
DOI	10.1186/s40635-016-0116-z
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Article ; Online: Neutrophil-derived miR-223 as local biomarker of bacterial peritonitis

Amy C. Brook / Robert H. Jenkins / Aled Clayton / Ann Kift-Morgan / Anne-Catherine Raby / Alex P. Shephard / Barbara Mariotti / Simone M. Cuff / Flavia Bazzoni / Timothy Bowen / Donald J. Fraser / Matthias Eberl

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract Infection remains a major cause of morbidity, mortality and technique failure in patients with end stage kidney failure who receive peritoneal dialysis (PD). Recent research suggests that the early inflammatory response at the site of infection ... ...

Abstract	Abstract Infection remains a major cause of morbidity, mortality and technique failure in patients with end stage kidney failure who receive peritoneal dialysis (PD). Recent research suggests that the early inflammatory response at the site of infection carries diagnostically relevant information, suggesting that organ and pathogen-specific “immune fingerprints” may guide targeted treatment decisions and allow patient stratification and risk prediction at the point of care. Here, we recorded microRNA profiles in the PD effluent of patients presenting with symptoms of acute peritonitis and show that elevated peritoneal miR-223 and reduced miR-31 levels were useful predictors of bacterial infection. Cell culture experiments indicated that miR-223 was predominantly produced by infiltrating immune cells (neutrophils, monocytes), while miR-31 was mainly derived from the local tissue (mesothelial cells, fibroblasts). miR-223 was found to be functionally stabilised in PD effluent from peritonitis patients, with a proportion likely to be incorporated into neutrophil-derived exosomes. Our study demonstrates that microRNAs are useful biomarkers of bacterial infection in PD-related peritonitis and have the potential to contribute to disease-specific immune fingerprints. Exosome-encapsulated microRNAs may have a functional role in intercellular communication between immune cells responding to the infection and the local tissue, to help clear the infection, resolve the inflammation and restore homeostasis.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Neutrophil-derived miR-223 as local biomarker of bacterial peritonitis.

Brook, Amy C / Jenkins, Robert H / Clayton, Aled / Kift-Morgan, Ann / Raby, Anne-Catherine / Shephard, Alex P / Mariotti, Barbara / Cuff, Simone M / Bazzoni, Flavia / Bowen, Timothy / Fraser, Donald J / Eberl, Matthias

Scientific reports

2019 Volume 9, Issue 1, Page(s) 10136

Abstract: Infection remains a major cause of morbidity, mortality and technique failure in patients with end stage kidney failure who receive peritoneal dialysis (PD). Recent research suggests that the early inflammatory response at the site of infection carries ... ...

Abstract	Infection remains a major cause of morbidity, mortality and technique failure in patients with end stage kidney failure who receive peritoneal dialysis (PD). Recent research suggests that the early inflammatory response at the site of infection carries diagnostically relevant information, suggesting that organ and pathogen-specific "immune fingerprints" may guide targeted treatment decisions and allow patient stratification and risk prediction at the point of care. Here, we recorded microRNA profiles in the PD effluent of patients presenting with symptoms of acute peritonitis and show that elevated peritoneal miR-223 and reduced miR-31 levels were useful predictors of bacterial infection. Cell culture experiments indicated that miR-223 was predominantly produced by infiltrating immune cells (neutrophils, monocytes), while miR-31 was mainly derived from the local tissue (mesothelial cells, fibroblasts). miR-223 was found to be functionally stabilised in PD effluent from peritonitis patients, with a proportion likely to be incorporated into neutrophil-derived exosomes. Our study demonstrates that microRNAs are useful biomarkers of bacterial infection in PD-related peritonitis and have the potential to contribute to disease-specific immune fingerprints. Exosome-encapsulated microRNAs may have a functional role in intercellular communication between immune cells responding to the infection and the local tissue, to help clear the infection, resolve the inflammation and restore homeostasis.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Animals ; Bacterial Infections/genetics ; Cross-Sectional Studies ; Escherichia coli Infections/genetics ; Extracellular Vesicles/genetics ; Female ; Genetic Markers ; Gram-Negative Bacterial Infections ; Humans ; Male ; Mice, Inbred C57BL ; MicroRNAs/genetics ; Middle Aged ; Neutrophils/physiology ; Peritoneal Dialysis/adverse effects ; Peritonitis/genetics ; Peritonitis/microbiology ; Reproducibility of Results ; Young Adult
Chemical Substances	Genetic Markers ; MIRN223 microRNA, human ; MicroRNAs
Language	English
Publishing date	2019-07-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-46585-y
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Article ; Online: Toll-Like Receptors 2 and 4 Are Potential Therapeutic Targets in Peritoneal Dialysis-Associated Fibrosis.

Raby, Anne-Catherine / Colmont, Chantal S / Kift-Morgan, Ann / Köhl, Jörg / Eberl, Matthias / Fraser, Donald / Topley, Nicholas / Labéta, Mario O

Journal of the American Society of Nephrology : JASN

2016 Volume 28, Issue 2, Page(s) 461–478

Abstract: Peritoneal dialysis (PD) remains limited by dialysis failure due to peritoneal membrane fibrosis driven by inflammation caused by infections or sterile cellular stress. Given the fundamental role of Toll-like receptors (TLRs) and complement in ... ...

Abstract	Peritoneal dialysis (PD) remains limited by dialysis failure due to peritoneal membrane fibrosis driven by inflammation caused by infections or sterile cellular stress. Given the fundamental role of Toll-like receptors (TLRs) and complement in inflammation, we assessed the potential of peritoneal TLR2, TLR4 and C5a receptors, C5aR and C5L2, as therapeutic targets in PD-associated fibrosis. We detected TLR2-, TLR4-, and C5aR-mediated proinflammatory and fibrotic responses to bacteria that were consistent with the expression of these receptors in peritoneal macrophages (TLR2/4, C5aR) and mesothelial cells (TLR2, C5aR). Experiments in knockout mice revealed a major role for TLR2, a lesser role for TLR4, a supplementary role for C5aR, and no apparent activity of C5L2 in infection-induced peritoneal fibrosis. Similarly, antibody blockade of TLR2, TLR4, or C5aR differentially inhibited bacteria-induced profibrotic and inflammatory mediator production by peritoneal leukocytes isolated from the peritoneal dialysis effluent (PDE) of noninfected uremic patients. Additionally, antibodies against TLR2, TLR4, or the coreceptor CD14 reduced the profibrotic responses of uremic leukocytes to endogenous components present in the PDE of noninfected patients. Enhancing TLR2-mediated inflammation increased fibrosis in vivo Furthermore, soluble TLR2 (sTLR2), a negative modulator of TLRs that we detected in PDE, inhibited PDE-induced, TLR2- or TLR4-mediated profibrotic responses. Notably, sTLR2 treatment markedly reduced Gram-positive and -negative bacteria-induced fibrosis in vivo, inhibiting proinflammatory and fibrotic genes without affecting infection clearance. These findings reveal the influence of peritoneal TLR2 and TLR4 on PD-associated fibrosis and describe a therapeutic strategy against fibrosis.
MeSH term(s)	Animals ; Humans ; Mice ; Mice, Knockout ; Peritoneal Dialysis/adverse effects ; Peritoneal Fibrosis/drug therapy ; Peritoneal Fibrosis/etiology ; Toll-Like Receptor 2/antagonists & inhibitors ; Toll-Like Receptor 4/antagonists & inhibitors
Chemical Substances	Tlr2 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 2 ; Toll-Like Receptor 4
Language	English
Publishing date	2016-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2015080923
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Article: Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk.

LeBouder, Emmanuel / Rey-Nores, Julia E / Raby, Anne-Catherine / Affolter, Michael / Vidal, Karine / Thornton, Catherine A / Labéta, Mario O

Journal of immunology (Baltimore, Md. : 1950)

2006 Volume 176, Issue 6, Page(s) 3742–3752

Abstract: The mechanisms controlling innate microbial recognition in the neonatal gut are still to be fully understood. We have sought specific regulatory mechanisms operating in human breast milk relating to TLR-mediated microbial recognition. In this study, we ... ...

Abstract	The mechanisms controlling innate microbial recognition in the neonatal gut are still to be fully understood. We have sought specific regulatory mechanisms operating in human breast milk relating to TLR-mediated microbial recognition. In this study, we report a specific and differential modulatory effect of early samples (days 1-5) of breast milk on ligand-induced cell stimulation via TLRs. Although a negative modulation was exerted on TLR2 and TLR3-mediated responses, those via TLR4 and TLR5 were enhanced. This effect was observed in human adult and fetal intestinal epithelial cell lines, monocytes, dendritic cells, and PBMC as well as neonatal blood. In the latter case, milk compensated for the low capacity of neonatal plasma to support responses to LPS. Cell stimulation via the IL-1R or TNFR was not modulated by milk. This, together with the differential effect on TLR activation, suggested that the primary effect of milk is exerted upstream of signaling proximal to TLR ligand recognition. The analysis of TLR4-mediated gene expression, used as a model system, showed that milk modulated TLR-related genes differently, including those coding for signal intermediates and regulators. A proteinaceous milk component of > or =80 kDa was found to be responsible for the effect on TLR4. Notably, infant milk formulations did not reproduce the modulatory activity of breast milk. Together, these findings reveal an unrecognized function of human milk, namely, its capacity to influence neonatal microbial recognition by modulating TLR-mediated responses specifically and differentially. This in turn suggests the existence of novel mechanisms regulating TLR activation.
MeSH term(s)	Cell Line ; Gene Expression Regulation/drug effects ; Hemocytes/drug effects ; Hemocytes/immunology ; Hemocytes/metabolism ; Humans ; Immunity, Innate/drug effects ; Immunity, Innate/immunology ; Infant Formula/pharmacology ; Infant, Newborn ; Lipopolysaccharides/pharmacology ; Milk, Human/immunology ; Receptors, Interleukin-1/metabolism ; Receptors, Tumor Necrosis Factor/metabolism ; Toll-Like Receptors/immunology ; Toll-Like Receptors/metabolism
Chemical Substances	Lipopolysaccharides ; Receptors, Interleukin-1 ; Receptors, Tumor Necrosis Factor ; Toll-Like Receptors
Language	English
Publishing date	2006-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.176.6.3742
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