title: Impact of toll-like receptor 4 deficiency on the response to uterine ischemia/reperfusion in mice.
abstract: Our objective was to determine the role of toll-like receptor 4 (TLR4) in uterine ischemia/reperfusion (I/R)-induced fetal growth restriction (FGR). Pregnant TLR4-deficient and wild-type mice were subjected to I/R or a sham procedure. Fetal and placental weights were recorded and tissues were collected. Pep-1 (inhibits low-molecular-weight hyaluronan (LMW-HA) binding to TLR4) was used to determine whether LMW-HA-TLR4 interaction has a role in FGR. TLR4-deficient mice exhibited significantly lower baseline fetal weights compared with wild-type mice (P<0.05), along with extensive placental calcification that was not present in wild-type mice. Following I/R, fetal and placental weights were significantly reduced in wild-type (P<0.05) but not in TLR4-deficient mice. However, I/R increased fetal loss (P<0.05) only in TLR4-deficient mice. Corresponding with the reduced fetal weights, uterine myeloperoxidase activity increased in wild-type mice (P<0.001), indicating an inflammatory response, which was absent in TLR4-deficient mice. TLR4 was shown to have a regulatory role for two anti-inflammatory cytokines: interferon-B1 decreased only in wild-type mice (P<0.01) and interleukin-10 increased only in TLR4-deficient mice (P<0.001), in response to I/R. Pep-1 completely prevented I/R-induced FGR (P<0.001), indicating a potential role for the endogenous TLR4 ligand LMW-HA in I/R-induced FGR. In conclusion, uterine I/R in pregnancy produces FGR that is dependent on TLR4 and endogenous ligand(s), including breakdown products of HA. In addition, TLR4 may play a role in preventing pregnancy loss after uterine I/R.
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. lthaete@northshore.org
authors.forename: Larry G
authors.initials: LG
authors.lastname: Thaete
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Qu
authors.forename: Tamas
authors.initials: T
authors.lastname: Jilling
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Philip
authors.initials: P
authors.lastname: Fitchev
authors.forename: Emmet
authors.initials: E
authors.lastname: Hirsch
authors.forename: Saira
authors.initials: S
authors.lastname: Khan
authors.forename: Mark G
authors.initials: MG
authors.lastname: Neerhof
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002114:Calcinosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005313:Fetal Death / Q000209:etiology; D005317:Fetal Growth Retardation / Q000209:etiology; D020567:Fetal Weight; D006820:Hyaluronic Acid / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000378:metabolism; D009929:Organ Size; D009195:Peroxidase / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014591:Uterine Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014599:Uterus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D008024:Ligands; D050505:Mutant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; D009195:Peroxidase