Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy.

TY - JOUR

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 -