Physiological TLR4 regulation in human fetal membranes as an explicative mechanism of a pathological preterm case.

Corinne Belville,Loïc Blanchon,Christelle Gross,Marion Rouzaire,Vincent Sapin,Bruno Pereira,Denis Gallot,Flora Ponelle-Chachuat

doi:10.7554/elife.71521

Abstract

The integrity of human fetal membranes is crucial for harmonious fetal development throughout pregnancy. Their premature rupture is often the consequence of a physiological phenomenon that has been exacerbated. Beyond all the implied biological processes, inflammation is of primary importance and is qualified as 'sterile' at the end of pregnancy. In this study, complementary methylomic and transcriptomic strategies on amnion and choriodecidua explants obtained from the altered (cervix zone) and intact fetal membranes at term and before labour were used. By cross-analysing genome-wide studies strengthened by in vitro experiments, we deciphered how the expression of toll-like receptor 4 (TLR4), an actor in pathological fetal membrane rupture, is controlled. Indeed, it is differentially regulated in the altered zone and between both layers by a dual mechanism: (1) the methylation of TLR4 and miRNA promoters and (2) targeting by miRNA (let-7a-2 and miR-125b-1) acting on the 3'-UTR of TLR4. Consequently, this study demonstrates that fine regulation of TLR4 is required for sterile inflammation establishment at the end of pregnancy and that it may be dysregulated in the pathological premature rupture of membranes.

Highlights

Placenta and fetal membranes are extra embryonic tissues that are originally formed by trophoblastic cell differentiation
At term without labour, here by classifying genes into specific biological processes, we demonstrated that toll-like receptor 4 (TLR4), which is classically involved in the recognition of Gram-n egative bacteria and that triggers an inflammatory response in chorioamnionitis leading to premature rupture of membranes (PPROM) (Medzhitov et al, 1997; Poltorak et al, 1998), was overexpressed in the zone of altered morphology (ZAM) choriodecidua compared with the ZAM amnion
After identifying the differentially hypermethylated genes between the amnion and choriodecidua on the whole genome between the zone of intact morphology (ZIM) and ZAM (Figure 1A), biological process analysis was performed; this has been represented by a four-w ay Venn diagram (Figure 1B)

Summary

Introduction

Placenta and fetal membranes are extra embryonic tissues that are originally formed by trophoblastic cell differentiation. The site of rupture is a particular and unique zone of altered morphology (ZAM) situated around the cervix (McLaren et al, 1999; McParland et al, 2003), which, along with a zone of intact morphology (ZIM), presents specific histological and cellular characteristics (El Khwad et al, 2006; Mauri et al, 2013; de Castro Silva et al, 2020).

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