Grant: Discovery Grants Program - Individual

The immune system of the uterine endometrium is exceptional in its ability to protect the mucosa from a variety of pathogens while being supportive to a developing semiallogeneic embryo. Inflammatory processes induced by host defense to infection, however, are a major challenge for the maternal immune system to successful pregnancy outcome. Tissue macrophages (MPhs) represent one of the most abundant populations of inflammatory cells in the human and the mouse uterus. In normal pregnancies, they support embryo implantation and placental differentiation. On the other hand, many effects of bacterial endotoxins in tissue injury are known to be induced through activation of tissue MPhs. Thus, it is not surprising that aberrant activation of inflammatory pathways in MPhs has been associated with early embryo loss in murine experimental models and in infection-induced abortion in humans. Because MPhs play such important functions in the uterine tissues, the cellular and molecular mechanisms underlying their differentiation and adaptation during gestation and infection need to be investigated in depth. We propose that the key modulators of uterine MPh functions are signaling factors produced by uterine epithelial cells. In fact, cytokines are the main inflammatory mediators produced within the uterine endometrium in response to infectious and embryonic signals. They act in complex networks to orchestrate local and systemic inflammatory responses required to protect the embryo from maternal immune rejection and invading pathogens. In the recent years, we have focused our efforts on studying the effect of the cytokine leukemia inhibitory factor (LIF) on MPh differentiation. LIF is highly expressed in the endometrial epithelium and is essential to embryo implantation in mice. In fact, LIF is a central regulator of local and systemic inflammatory responses. LIF provides protection against endotoxin-induced tissue pathology by enhancing the expression of hepatic acute-phase proteins. In the pregnant uterus, LIF is most likely playing a role as a mediator molecule in the protective effect of progesterone against endotoxin-induced fetal demise. Moreover, in response to LIF stimulation, uterine/decidual tissues express oncostatin M (OSM) and amphiregulin (AREG), which are key mediators of the acute-phase protein synthesis regulation. Indeed, in the liver, LIF and OSM are among the major inducers of the hepatic acute-phase gene expression while, in contrast, AREG is a negative regulator of the acute-phase reaction. However, the roles of LIF, OSM and AREG in modulating endotoxin-mediated MPh activation and the acute-phase response to endotoxins during pregnancy remain to be elucidated.Thus, the overall research program of my laboratory is to investigate and understand the role of uterine signaling factors in the orchestration of local and systemic inflammatory responses at the interface of reproductive and immune systems. On the basis of above observations, our general working hypothesis is that, in order to protect the uterus and the developing embryo, LIF is critical to direct the spatiotemporal differentiation of tissue MPhs in the uterus and the acute-phase response in the liver. In addition, we propose that this immune-modulating effect will vary during the estrous cycle and early pregnancy in response to fluctuating estradiol and progesterone levels. By using the LIF knockout mouse model and analyzing cycling and pregnant animals, we propose the following specific objectives: 1) Investigate the role of LIF and female sex hormones in regulating the process of uterine MPh activation during endotoxin-mediated inflammation; and 2) Determine the mechanisms by which LIF protects the host and the embryo against endotoxin-mediated tissue injury.