Pathophysiological Implication of Pattern Recognition Receptors in Fetal Membranes Rupture: RAGE and NLRP Inflammasome

Abstract

Preterm prelabor ruptures of fetal membranes (pPROM) are a pregnancy complication responsible for 30% of all preterm births. This pathology currently appears more as a consequence of early and uncontrolled process runaway activation, which is usually implicated in the physiologic rupture at term: inflammation. This phenomenon can be septic but also sterile. In this latter case, the inflammation depends on some specific molecules called “alarmins” or “damage-associated molecular patterns” (DAMPs) that are recognized by pattern recognition receptors (PRRs), leading to a microbial-free inflammatory response. Recent data clarify how this activation works and which receptor translates this inflammatory signaling into fetal membranes (FM) to manage a successful rupture after 37 weeks of gestation. In this context, this review focused on two PRRs: the receptor for advanced glycation end-products (RAGE) and the NLRP7 inflammasome.

Development of oxidative stress‐associated disease models using feto‐maternal interface organ‐on‐a‐chip

“…Intra-amniotic OS, the production of reactive oxygen species (ROS), and sterile inflammation at term and preterm are well-reported phenomena. 6,10,22,[86][87][88][89] In vitro cultures of amnion and chorion cells and ex vivo fetal membrane explant cultures have documented the following multiple biological processes and signaling pathways related to intra-amniotic oxidative imbalance-associated pathologies (i.e., ROS production, DNA fragmentation, p38MAPK activation, EMT, senescence, and inflammation) 21,22,25,27,28,32,50,73,[90][91][92][93][94][95][96] that shift immune status to a pro-inflammatory environment. Changes in the inflammatory environment at the choriodecidua interface have been associated with the suppression of anti-inflammatory hormone (i.e., progesterone) and immune cell regulators (i.e., HLAs) that allow for maternal immune cell infiltration into the membranes.…”

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“…The involvement of RAGE in the progression of inflammatory and neurodegenerative disorders has been well studied. Inflammation plays a central role in many physiological processes that are important in the progression of diabetes, lung diseases, and fetal membrane weakening, which are characterized by elevated levels of RAGE in circulation [ 19 , 24 , 25 ]. RAGE exerts its physiological and pathological effects through its ability to bind with a multitude of ligands.…”

“…Increasingly, it is becoming accepted that RAGE signaling plays a significant role in driving the inflammation that leads to the rupture of the human fetal membranes (FMs) [ 20 , 25 ]. Indeed, this outcome is dependent on the sophisticated communication between the uterus, placenta, and FM, as RAGE signal transduction flows from maternal to fetal tissues, and back again.…”

“…Thus, inflammation is necessary for many of the key parturition pathways, including fetal membrane weakening, regardless of whether it occurs at the end of normal gestation or preterm (<37 weeks of gestation). RAGE signaling is influential for both preterm and full-term pregnancies’ FM weakening and rupture via its ligand HMGB1 [ 20 , 25 ]. Its binding to RAGE has been identified as an activator of NF-κB, which leads to a release of inflammatory cytokines, such as Interleukin-6 (IL6), Granulocyte Macrophage Stimulating Factor (GM-CSF), and Tumor Necrosis Factor Alpha (TNF-α).…”

“…Multiple polymorphisms for the receptor have also been identified; however, the most studied, Gly82Ser, is a single-nucleotide polymorphism within the RAGE gene that modifies the ligand-binding structure by increasing its binding affinity for AGEs. This genotype is characterized by lower sRAGE levels and higher risk factors for CVD, which has implicated it in diabetes and autoimmune diseases, such as Kawasaki disease [ 25 ]. Thus, abnormal upregulation and sRAGE activation are indicative of disease development and inflammatory and immune responses in the body [ 28 , 103 , 152 , 153 ].…”