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

更好地了解导致子痫前期发展的病理生理机制对于制定新的预防和治疗策略至关重要。滋养层的活动和侵袭对胎盘发育至关重要；这一过程的异常可能导致病理性妊娠和先兆子痫。胎盘巨噬细胞，霍夫鲍尔细胞，调节滋养层活性，这两种细胞之间的直接或间接接触对成功妊娠至关重要。在前期工作中，我们发现CD74在子痫前期胎盘中下调，在巨噬细胞中定位CD74。此外，CD74的下游靶因子在子痫前期胎盘中也受到抑制。我们提出CD74参与先兆子痫的发展，并且是控制滋养细胞和巨噬细胞之间细胞间相互作用的潜在候选基因。因此，研究CD74和巨噬细胞-滋养细胞在妊娠和子痫前期的相互作用对于增强我们对其作用方式的认识和评估其作为子痫前期治疗药物的潜力是至关重要的。我们的总体假设是胎盘巨噬细胞中CD74表达下调是导致子痫前期的潜在病理机制。具体而言，我们将追求以下目标：目标1：我们将确定CD74下调在子痫前期胎盘中的潜在机制。目的2：我们将研究CD74下调对巨噬细胞-滋养细胞相互作用的功能影响。目的3：我们将在动物模型中确定CD74下调的后果。创新：我们将首次揭示CD74在巨噬细胞-滋养细胞相互作用和子痫前期发病机制中的影响。我们的发现可能会为这种毁灭性疾病带来新的机制和治疗途径。

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.