|About the Book|
Early and late term pregnancy maladies are thought to correlate with infection and inflammation at the maternal-fetal interface. Infectious agents may manifest systemically or through intrauterine routes, and are often present at sub-clinical levels.MoreEarly and late term pregnancy maladies are thought to correlate with infection and inflammation at the maternal-fetal interface. Infectious agents may manifest systemically or through intrauterine routes, and are often present at sub-clinical levels. Consequently, their ability to initiate adverse pregnancy outcomes and the mechanisms that facilitate resultant pregnancy disorders remain largely unknown.-A delicate juxtaposition exists at the maternal-fetal interface composed of a tightly regulated pro- and anti-inflammatory milieu that simultaneously allows placental growth and protection of the fetal-allograft. Interleuikin-10 (IL-10) and Toll-like receptors (TLRs) are key components that contribute to the maintenance of equilibrium throughout pregnancy. IL-10 is a regulatory cytokine produced by the majority of cells at the maternal-fetal interface. TLRs, ubiquitous at the maternal-fetal interface, are innate immune sentinel receptors evolved to recognize pathogen associated molecular patterns (PAMPs). The central hypothesis of this work is that IL-10 deficiency coupled with an inflammatory insult may lead to adverse pregnancy outcomes mediated by dysregulation of uterine immunity through pathogenic activation of TLRs.-This work explores dysregulation of the uterine immune system in response to agonists for TLR-3, TLR-4, and TLR-9. IL-10-/- and wild type (WT) mice are utilized in a pregnancy model in order to delineate the role of pathogenic TLR activation. We show that, in IL-10-/- mice, TLR-9 activation induces a unique immune cascade marked by production of mKC, neutrophil and macrophage placental influx, and adverse pregnancy outcomes mediated by a TNF-alpha-macrophage axis. In contrast, we demonstrate that TLR-3-mediated immune dysregulation is not dependent on the availability of IL-10. Rather, in response to TLR-3 activation, IL-10 deficiency leads to an alternative program of cellular response as fetal resorption in WT mice is mediated by a uNK-TNF-alpha-axis, while IL-10-/- mice experience fetal demise as a result of a T-cell-TNF-alpha axis. Finally, we show that intrauterine administration of TLR-4 agonist causes detrimental effects to the ipsilateral versus contralateral horn marked by uNK cell-mediated placental pathology in the ipsilateral horn only. Taken together, these findings elucidate novel cellular mechanisms at the maternal-fetal interface that induce adverse pregnancy outcomes in response to bacterial and viral mimics.