Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

Ella Shana Green, Petra Clara Arck, Ella Shana Green, Petra Clara Arck

Abstract

Preterm birth (PTB) complicates 5-18% of pregnancies globally and is a leading cause of maternal and fetal morbidity and mortality. Most PTB is spontaneous and idiopathic, with largely undefined causes. To increase understanding of PTB, much research in recent years has focused on using animal models to recapitulate the pathophysiology of PTB. Dysfunctions of maternal immune adaptations have been implicated in a range of pregnancy pathologies, including PTB. A wealth of evidence arising from mouse models as well as human studies is now available to support that PTB results from a breakdown in fetal-maternal tolerance, along with excessive, premature inflammation. In this review, we examine the current knowledge of the bidirectional communication between fetal and maternal systems and its role in the immunopathogenesis of PTB. These recent insights significantly advance our understanding of the pathogenesis of PTB, which is essential to ultimately designing more effective strategies for early prediction and subsequent prevention of PTB.

Keywords: Fetal signals; Inflammatory signaling pathways; Labor; Microbiome; Mouse models; Preterm birth; Regulatory T cells.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Milestones of pregnancy and related immune and endocrine adaptations. Normally progressing pregnancies result from the successful orchestration of processes involved in peri-conception, implantation, decidualization, and placentation. Hormone signaling, in particular, progesterone (P4), establishes a receptive endometrium and decidual quiescence; maternal immune tolerance mitigates the risk for fetal rejection and supports spiral artery remodeling and placentation. The onset of parturition is characterized by a switch in the local immune environment from a tolerogenic state to an activation state, a reversal of decidual quiescence in favor of myometrial activation, and a withdrawal of P4 signaling. Maternal and paternal lifestyle factors (such as stress and nutrition), environmental factors, age, ethnicity, and genetics contribute to the success or failure of pregnancy, including the risk for PTB [9, 12, 13]
Fig. 2
Fig. 2
Trajectories of maternal immune tolerance versus inflammation determines the susceptibility to PTB. A balanced tolerogenic and inflammatory immune response underlies the normal progressing of pregnancy and onset of birth at term. Failure to mount sufficient levels of tolerance (top panel) or excess inflammation (middle panel) creates an immune imbalance in favor of inflammation, thereby increasing the risk for PTB
Fig. 3
Fig. 3
Current understanding of the inflammatory pathways of parturition. In pregnancy, toll-like receptors (TLRs) expressed on immune and endothelial cells at the fetal-maternal-interface are activated during sterile or active inflammation, via a range of DAMPs and PAMPs. TLR activation causes a cascade of intracellular signaling events leading to inflammasome activation and release of pro-inflammatory cytokines and chemokines. This leads to further recruitment of pro-inflammatory leukocytes such as macrophages, monocytes, neutrophils, and T cells to the decidua, placenta, and amniotic cavity. In macrophages, NF-κb activation controls expression of genes encoding uterine contractility and cervical ripening proteins such as prostaglandins F2α receptor, connexin-43, oxytocin receptor, and cyclooxygenase 2 (COX-2), as well as genes encoding pro-inflammatory cytokines TNFα, IL1β, IL6, and IL8. Uterine contractility and cervical ripening lead to membrane rupture and subsequently, the onset of labor. Withdrawal of P4 signaling, myometrial activation, fetal signals, and a switch in maternal immune phenotypes from tolerance to inflammation all contribute to the activation of the main inflammatory pathway. In the case of preterm birth, studies in mice show that various perturbations in this inflammatory pathway can occur, leading to premature activation of essential pathways components, resulting in preterm labor
Fig. 4
Fig. 4
Fetal-maternal crosstalk is dysregulated in preterm versus normal pregnancy. Fetal-maternal crosstalk is essential for the progression of normal pregnancy. Via the placenta, nutrients, oxygen, and maternal antibodies are transferred to the fetus, and fetal metabolic waste is transferred to the mother. In addition, bidirectional transfer of key signaling molecules and cells occurs, such as the transfer of hormones, cytokines, nucleic acids, extracellular vesicles (ECVs), and microchimeric fetal and maternal cells. These molecules and cells influence both maternal and fetal immune environments. In the fetus, interactions between fetal immune cells and maternal MC cells induce fetal T cell tolerance to maternal antigens. As the fetus matures, the fetal lung and adrenal gland signal for parturition through fetal macrophages, which drive inflammation in the amniotic cavity. Approaching parturition, the decidual immune environment reflects interactions between various cells including macrophages, monocytes and T cells, and decidual endothelial and stromal cells. Decreased Treg cell activity may result in activation of fetal antigen-specific Teff cells. Fetal MC cells may provide a source of fetal antigen in the decidua. These cells respond to increasing inflammatory signals via PAMPs, DAMPs, and cytokines drive an inflammatory immune response that leads to the induction of labor. In preterm labor, various components of fetal-maternal crosstalk can be dysregulated, leading to premature activation of the inflammatory pathways off labor. This may occur due to a breakdown in fetal-maternal tolerance, whereby maternal T cells are activated towards fetal antigens, or fetal T cells are activated against maternal antigens

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