Étude de l’inflammation placentaire lors de complications de la grossesse
The placenta is the central organ of pregnancy and its adequate functioning is essential to ensure term delivery without complications. Inflammation plays a key role in every step of pregnancy, from implantation to delivery. When this inflammation is unbalanced in the placenta, it can alter its functions. Inflammation can be induced by two different stimuli, either by external intervention like an infection (with Pathogen-Associated Molecular Patterns, PAMPs), or endogenously (with Damage-Associated Molecular Patterns, DAMPs). Increased inflammation is also associated with pregnancy complications and they affect 5-12% of all pregnancies and can have deleterious effects on maternal and infant health. These complications include preeclampsia (PE), preterm birth (PTB) and intrauterine growth restriction (IUGR). Even if these pathologies have different etiologies, they share a common factor that plays an essential role, inflammation. In order to better understand the role and the effects of inflammation on the human placenta and in pregnancy complications, we have evaluated the effects of classical PAMP (LPS) and DAMP (IL-1) on human placental explant model and we have realized an unbiased transcriptomic study of the placentas from each pregnancy complication. First of all, we demonstrated that LPS induced a higher production of pro-inflammatory cytokines compared to IL-1 and by inhibiting the IL-1 pathway using its antagonist (IL-1Ra), we decreased their expression and their secretion. Moreover, LPS treatment induced more cell death in the explants and proliferation of Hofbauer cells, macrophages of the placenta. Thereafter, transcriptomic study of placentas from pregnancy complications (PE, PTB and IUGR) allowed us to demonstrate that the pathologies were not clustering together based on their global gene expression compared to placentas from uncomplicated pregnancies which the majority of them were clustering together. It was possible to identify genes that were significantly modulated in each pathology and their gene ontology. We identified 198 genes common to all pregnancy complications and they were mostly related to inflammatory processes like interaction between lymphoid and non-lymphoid cells, leukocyte activation and regulation of cytokine production. Finally, in addition to confirming gene modulations previously known in each pregnancy complications, we were able to identify new genes that have never been associated with the pathologies such as FUT9, SLAMF7 and TGM3. To conclude, the work presented in this thesis show that inflammation induced by LPS and IL-1 did not have the same effect on the placenta. Inflammation is a key component to pregnancy complications and a better understanding of the inflammatory processes modulated in every pathology could help the development of new therapeutic strategies. Future work could investigate the proliferative potential of the Hofbauer cells and explore the new genes identified by the transcriptomic results.
inflammation PAMPs DAMPs placenta pregnancy pregnancy complications