Abstract
Gestational age-dependent immune intolerance at the maternal-fetal interface might be a contributing factor to placental pathology and adverse pregnancy outcomes. Although the intrauterine setting is highly choreographed and considered to be a protective environment for the fetus, unscheduled inflammation might overwhelm the intrauterine milieu to cause a cascade of events leading to adverse pregnancy outcomes. The old paradigm of a sterile intrauterine microenvironment has been challenged, and altered microflora has been detected in gestational tissues and amniotic fluid in the absence of induction of significant inflammation. Is there a role for endotoxin tolerance at the maternal-fetal interface? Endotoxin tolerance is a phenomenon in which tissues or cells exposed to the bacterial product, particularly lipopolysaccharide, become less responsive to subsequent exposures accompanied by decreased expression of pro-inflammatory mediators. This could also be related to trained or experienced immunity that leads to the successful outcome of subsequent pregnancies. Adaptation to endotoxin tolerance or trained immunity might be critical in preventing rejection of the fetus by the maternal immune system and protecting the fetus from excessive maternal inflammatory responses to infectious agents; however, to date, the exact mechanisms contributing to the establishment and maintenance of tolerance at the maternal-fetal interface remain incompletely understood. There is now extensive evidence suggesting that microRNAs (miRNAs) play important roles in the maintenance of a healthy pregnancy. miRNAs not only circulate freely in extracellular fluids but are also packaged within extracellular vesicles (EVs) produced by various cells and tissues. The placenta is a known, abundant, and transient source of EVs; therefore, our proposed model suggests that repeated exposure to infectious agents induces a tolerant phenotype at the maternal-fetal interface mediated by specific miRNAs mostly contained within placental EVs. We hypothesize that impaired endotoxin tolerance or failed trained immunity at the maternal-fetal interface will result in a pathological inflammatory response contributing to early or late pregnancy maladies.
Highlights
Our current understanding of immunity at the maternal-fetal interface has been shaped by acceptance of periodic concepts and approaches formed based on tissue-allograft studies in nonpregnant individuals, male or female, and by the paradigm suggesting the uterus as a sterile organ [1, 2]
Because miRNAs are included as cargo in extracellular vesicle (EV), do placental EVs and their embedded miRNA cargo play a role in immune tolerance at the maternal-fetal interface? This review focuses on immune tolerance at the maternal-fetal interface and reviews the role of miRNA in mediating immune tolerance via EVs in gestational tissues
Our lab demonstrated that endotoxin tolerance exists in placental tissues [109] and we proposed a model of miRNAmediated placental immune tolerance packaged within EVs
Summary
Our current understanding of immunity at the maternal-fetal interface has been shaped by acceptance of periodic concepts and approaches formed based on tissue-allograft studies in nonpregnant individuals, male or female, and by the paradigm suggesting the uterus as a sterile organ [1, 2]. This inflammatory process needs to be tightly regulated since such inflammation left unchecked can cause extensive tissue injury, septic shock, and death In the placenta, this resultant maternal-fetal inflammation is suggested to contribute to various adverse pregnancy outcomes, including placental dysfunction, preeclampsia, intrauterine growth restriction, and preterm labor [23]. This resultant maternal-fetal inflammation is suggested to contribute to various adverse pregnancy outcomes, including placental dysfunction, preeclampsia, intrauterine growth restriction, and preterm labor [23] Attenuation of this inflammation at the maternal-fetal interface can play a key role in fetal health and survival. The mechanisms of exosomes biogenesis and release continue to be investigated, little is known regarding how exosomes’ content is FIGURE 1 | Hypothetical illustration showing LPS mediated inflammatory response, possible mechanism of anti-inflammatory miRNAs mediated endotoxin tolerance as well as packaging within extracellular vesicles (EVs; including exosomes and microvesicles) in a placental trophoblast. Other examples of EV targets include cancer cells, which subsequently use EVs to target other organs, such as the lung and liver, to identify pre-metastatic niches based on specific integrin composition [108]
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