Dysregulated CD74 in macrophage-trophoblastic interactions and the pathogenesis of preeclampsia

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A better understanding of pathophysiologic mechanisms that lead to the development of preeclampsia is essential to develop new strategies for the prevention and the treatment. Trophoblastic activity and invasion are crucial to placental development; aberrancies in this process could lead to a pathological pregnancies and preeclampsia. Placental macrophages, the Hofbauer cells, regulate trophoblastic activity and direct or indirect contact between both cell types is essential for successful pregnancy. In preliminary work, we showed that the cluster of differentiation 74 (CD74) is downregulated in the preeclamptic placenta and localized CD74 in macrophages. Furthermore, downstream target factors of CD74 were also suppressed in the preeclamptic placenta. We propose that CD74 is involved in the development of preeclampsia and is a potential candidate for controlling cell-cell interaction between trophoblasts and macrophages. Thus, studies on CD74 and the macrophage-trophoblast interaction in pregnancy and preeclampsia are essential to enhance our knowledge of its modes of action and to evaluate its potential as a therapeutic agent in preeclampsia. Our global hypothesis is that a downregulated CD74 expression in placental macrophages is an underlying pathologic mechanism leading to preeclampsia. Specifically, we will pursue the following objectives: Objective 1:We will determine the underlying mechanisms of CD74 downregulation in the preeclamptic placenta. Objective 2:We will investigate the functional consequence of the CD74 downregulation on the macrophage-trophoblast interaction. Objective 3:We will determine the consequence of a CD74 downregulation in an animal model.Innovation:We will be the first to reveal the impact of CD74 in the macrophage-trophoblast interaction and the pathogenesis of preeclampsia, respectively. Our findings could lead to new mechanistic and therapeutic avenues for this devastating disease.