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Type: Journal article
Title: Toll-like receptor-4 null mutation causes fetal loss and fetal growth restriction associated with impaired maternal immune tolerance in mice.
Author: Chan, H.Y.
Moldenhauer, L.M.
Groome, H.M.
Schjenken, J.E.
Robertson, S.A.
Citation: Scientific Reports, 2021; 11(1):1-17
Publisher: Springer Nature
Issue Date: 2021
ISSN: 2045-2322
Statement of
Hon Y. Chan, Lachlan M. Moldenhauer, Holly M. Groome, John E. Schjenken, Sarah A. Robertson
Abstract: Maternal immune adaptation to accommodate pregnancy depends on sufficient availability of regulatory T (Treg) cells to enable embryo implantation. Toll-like receptor 4 is implicated as a key upstream driver of a controlled inflammatory response, elicited by signals in male partner seminal fluid, to initiate expansion of the maternal Treg cell pool after mating. Here, we report that mice with null mutation in Tlr4 (Tlr4-/-) exhibit impaired reproductive outcomes after allogeneic mating, with reduced pregnancy rate, elevated mid-gestation fetal loss, and fetal growth restriction, compared to Tlr4+/+ wild-type controls. To investigate the effects of TLR4 deficiency on early events of maternal immune adaptation, TLR4-regulated cytokines and immune regulatory microRNAs were measured in the uterus at 8 h post-mating by qPCR, and Treg cells in uterus-draining lymph nodes were evaluated by flow cytometry on day 3.5 post-coitum. Ptgs2 encoding prostaglandin-endoperoxide synthase 2, cytokines Csf2, Il6, Lif, and Tnf, chemokines Ccl2, Cxcl1, Cxcl2, and Cxcl10, and microRNAs miR-155, miR-146a, and miR-223 were induced by mating in wild-type mice, but not, or to a lesser extent, in Tlr4-/- mice. CD4⁺ T cells were expanded after mating in Tlr4+/+ but not Tlr4-/- mice, with failure to expand peripheral CD25⁺FOXP3⁺ NRP1⁻ or thymic CD25⁺FOXP3⁺ NRP1⁺ Treg cell populations, and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. We conclude that TLR4 is an essential mediator of the inflammation-like response in the pre-implantation uterus that induces generation of Treg cells to support robust pregnancy tolerance and ensure optimal fetal growth and survival.
Keywords: Animals
Chemotaxis, Leukocyte
Cyclooxygenase 2
Fetal Growth Retardation
Fetal Resorption
Gestational Age
Loss of Function Mutation
Lymph Nodes
Lymphocyte Activation
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Organ Size
Pregnancy Outcome
Pregnancy Rate
Pregnancy, Animal
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
Toll-Like Receptor 4
Rights: © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
DOI: 10.1038/s41598-021-95213-1
Grant ID:
Appears in Collections:Biochemistry publications

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