Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy.
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Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy. / Friebe, Astrid; Douglas, Alison J; Solano, Maria Emilia; Blois, Sandra M; Hagen, Evelin; Klapp, Burghard F; Clark, David A; Arck, Petra.
in: J MOL MED, Jahrgang 89, Nr. 7, 7, 2011, S. 689-699.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy.
AU - Friebe, Astrid
AU - Douglas, Alison J
AU - Solano, Maria Emilia
AU - Blois, Sandra M
AU - Hagen, Evelin
AU - Klapp, Burghard F
AU - Clark, David A
AU - Arck, Petra
PY - 2011
Y1 - 2011
N2 - Maternal stress can cause loss of both histocompatible (syngeneic) and histoincompatible (semiallogeneic) embryos in pregnant mice. Stress increases abortogenic Th1 cytokines and reduces levels of anti-abortogenic Th2 cytokines, progesterone levels, and T regulatory cell activity. While physiological levels of interferon-? promote vascular remodeling at the feto-maternal interface, an overshooting Th1 cytokine response requires a Toll-like receptor (TLR)-mediated "danger signal" such as lipopolysaccharide (LPS). Interestingly, stress can enhance permeability of mucosal membranes to entry of bacterial products and promote transmucosal migration of commensal bacteria. We hypothesized that bacterial component such as LPS may provide the danger signal through which stress triggers maternal immune activation, subsequently resulting in fetal rejection. Blocking the TLR4 receptor for LPS or neutralization of LPS using bactericidal permeability increasing protein abrogate fetal loss due to sonic stress challenge in DBA/2J-mated CBA/J mice. These treatments prevented stress-triggered immune responses in the decidua, upregulated Treg cells, and reduced the frequency of mature dendritic cells in uterine-draining lymph nodes but not in the uterus. Interestingly, anti-TLR4 treatment only partly ameliorated stress-induced endocrine responses, such as increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression but not decrease of serum progesterone. Galectin-1 knock-out mice were more susceptible to stress-triggered complete implantation failure rather than fetal loss, which was also abolished by LPS neutralization. Insights provided in this paper shed new light on the mechanisms by which stress affects pregnancy outcome and introduce microbial-derived LPS as a mediator within the cascade of stress-triggered immune and endocrine events during pregnancy.
AB - Maternal stress can cause loss of both histocompatible (syngeneic) and histoincompatible (semiallogeneic) embryos in pregnant mice. Stress increases abortogenic Th1 cytokines and reduces levels of anti-abortogenic Th2 cytokines, progesterone levels, and T regulatory cell activity. While physiological levels of interferon-? promote vascular remodeling at the feto-maternal interface, an overshooting Th1 cytokine response requires a Toll-like receptor (TLR)-mediated "danger signal" such as lipopolysaccharide (LPS). Interestingly, stress can enhance permeability of mucosal membranes to entry of bacterial products and promote transmucosal migration of commensal bacteria. We hypothesized that bacterial component such as LPS may provide the danger signal through which stress triggers maternal immune activation, subsequently resulting in fetal rejection. Blocking the TLR4 receptor for LPS or neutralization of LPS using bactericidal permeability increasing protein abrogate fetal loss due to sonic stress challenge in DBA/2J-mated CBA/J mice. These treatments prevented stress-triggered immune responses in the decidua, upregulated Treg cells, and reduced the frequency of mature dendritic cells in uterine-draining lymph nodes but not in the uterus. Interestingly, anti-TLR4 treatment only partly ameliorated stress-induced endocrine responses, such as increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression but not decrease of serum progesterone. Galectin-1 knock-out mice were more susceptible to stress-triggered complete implantation failure rather than fetal loss, which was also abolished by LPS neutralization. Insights provided in this paper shed new light on the mechanisms by which stress affects pregnancy outcome and introduce microbial-derived LPS as a mediator within the cascade of stress-triggered immune and endocrine events during pregnancy.
KW - Animals
KW - Female
KW - Mice
KW - Mice, Knockout
KW - Pregnancy
KW - Signal Transduction/drug effects/immunology
KW - Progesterone/metabolism
KW - Mice, Inbred CBA
KW - Adjuvants, Immunologic/pharmacology
KW - Antibodies, Blocking/immunology/pharmacology
KW - Antibodies, Neutralizing/immunology/metabolism
KW - Antimicrobial Cationic Peptides/pharmacology
KW - Blood Proteins/pharmacology
KW - Fetal Death/immunology/prevention & control
KW - Galectin 1/metabolism
KW - Hypothalamo-Hypophyseal System/metabolism
KW - Inflammation/immunology/metabolism
KW - Lipopolysaccharides/antagonists & inhibitors/immunology/pharmacology
KW - Mice, Inbred DBA
KW - Pituitary-Adrenal System/metabolism
KW - Stress, Physiological/drug effects
KW - Toll-Like Receptor 4/antagonists & inhibitors/metabolism
KW - Animals
KW - Female
KW - Mice
KW - Mice, Knockout
KW - Pregnancy
KW - Signal Transduction/drug effects/immunology
KW - Progesterone/metabolism
KW - Mice, Inbred CBA
KW - Adjuvants, Immunologic/pharmacology
KW - Antibodies, Blocking/immunology/pharmacology
KW - Antibodies, Neutralizing/immunology/metabolism
KW - Antimicrobial Cationic Peptides/pharmacology
KW - Blood Proteins/pharmacology
KW - Fetal Death/immunology/prevention & control
KW - Galectin 1/metabolism
KW - Hypothalamo-Hypophyseal System/metabolism
KW - Inflammation/immunology/metabolism
KW - Lipopolysaccharides/antagonists & inhibitors/immunology/pharmacology
KW - Mice, Inbred DBA
KW - Pituitary-Adrenal System/metabolism
KW - Stress, Physiological/drug effects
KW - Toll-Like Receptor 4/antagonists & inhibitors/metabolism
U2 - 10.1007/s00109-011-0743-5
DO - 10.1007/s00109-011-0743-5
M3 - SCORING: Journal article
VL - 89
SP - 689
EP - 699
JO - J MOL MED
JF - J MOL MED
SN - 0946-2716
IS - 7
M1 - 7
ER -