Adverse Interaction Between Iron Deficiency and Inflammation in Pregnancy

孕期充足的铁供应对胎儿发育和产妇健康至关重要。缺铁及其最常见的表现是贫血，在怀孕期间非常普遍，可能对母亲和胎儿产生不利影响。妊娠期间的全身性母体炎症也很常见，要么是由感染(细菌、病毒、寄生虫)引起的，要么是伴随着肥胖、糖尿病和自身免疫性疾病等慢性疾病。与炎症妊娠相关的不良后果包括自然流产、早产、宫内生长受限、胎儿死亡、大体发育异常和后代的自闭症行为。我们在小鼠身上的初步研究表明，母亲缺铁和炎症之间存在令人惊讶的协同不利相互作用，导致胚胎毒性，这在任何一种情况下都没有观察到。与铁状态正常的母鼠相比，在注射脂多糖引起的急性母体炎症的背景下，缺铁的母鼠胚胎异常的发生率明显更高。我们的目标是确定这种协同作用的潜在机制：目的1.确定缺铁对母体、胎盘和胚胎炎症的影响。利用我们的脂多糖引发炎症的小鼠模型，我们将检查怀孕期间缺铁是否会增强促炎反应或改变母亲、胎盘和胚胎中的免疫细胞数量。目的2.基于人和小鼠胎盘组织中肿瘤坏死因子受体1与肿瘤坏死因子受体1之间的强相关性，我们推测细胞铁状态调节肿瘤坏死因子受体1的水平。我们将定义在缺铁时增加TNFR1的特定胎盘细胞类型，并研究调节TNFR1的候选机制。。目的3.确定肿瘤坏死因子途径在体内不良协同作用中的作用-我们的初步数据表明，肿瘤坏死因子α-肿瘤坏死因子受体途径在介导缺铁性炎性妊娠的不良结局中起着重要作用。我们将使用内皮细胞或滋养层细胞特异性缺乏TNFR1的小鼠来确定在急性炎症模型中是否需要肿瘤坏死因子途径来实现不利的协同作用。目的4.明确缺铁对胎盘细胞转录组的影响。我们将用无偏倚的单细胞RNAseq补充我们的候选人驱动的方法，对缺铁和富铁妊娠的小鼠胎盘进行脂多糖治疗，以详细了解缺铁如何改变胎盘细胞群以及它们在应对炎症时的转录活性。我们的建议分析了缺铁和炎症之间的一种新的相互作用。考虑到这种组合障碍在怀孕妇女中的高全球流行率，该课题具有突出的翻译重要性，我们的研究可以帮助解释通常观察到的不良后果。从长远来看，我们的发现有可能影响铁和妊娠炎症性疾病的治疗。

Adequate iron availability during pregnancy is essential for fetal development and maternal health. Iron deficiency and its most common manifestation, anemia, are highly prevalent during pregnancy and can have adverse effects on the mother and the fetus. Systemic maternal inflammation during pregnancy is also quite common, and either results from infections (bacterial, viral, parasitic), or accompanies chronic conditions including obesity, diabetes, and autoimmune diseases. Adverse outcomes associated with inflamed pregnancies include spontaneous abortion, preterm labor, intrauterine growth restriction, fetal death, gross developmental abnormalities and autistic behaviors in offspring. Our preliminary studies in mice demonstrated a surprising synergistic adverse interaction between maternal iron deficiency and inflammation that led to embryotoxicity which was not observed with either condition alone. Compared to dams with normal iron status, those that were iron-deficient had significantly higher frequency of embryo abnormalities in the setting of acute maternal inflammation caused by LPS injection. We aim to define the underlying mechanisms of this synergy: Aim 1. Determine the effect of iron deficiency on maternal, placental and embryo inflammation. Using our mouse models of LPS-triggered inflammation, we will examine whether iron deficiency in pregnancy enhances pro-inflammatory response or alters immune cell census in the mother, placenta and embryo. Aim 2. Characterize the iron-dependent regulation of TNF receptor 1 Based on the strong correlation between placental TNFR1 and TFR1 in both humans and mice, we hypothesize that cellular iron status regulates TNFR1 levels. We will define the specific placental cell type that increases TNFR1 in response to iron deficiency, and examine candidate mechanisms regulating TNFR1. . Aim 3. Determine the role of the TNF pathway in adverse synergy in vivo—Our preliminary data implicated TNFα-TNFR pathway in mediating adverse outcomes in iron-deficient inflamed pregnancies. We will use mice with endothelial- or trophoblast-specific deficiency of TNFR1 to determine whether the TNF pathway is required for the adverse synergy in the model of acute inflammation. Aim 4. Define the effect of iron deficiency on placental cellular transcriptome. We will complement our candidate-driven approaches with an unbiased single-cell RNAseq on mouse placentas from iron-deficient and iron-replete pregnancies treated with LPS to gain detailed insight into how iron deficiency alters placental cell populations as well as their transcriptional activity in response to inflammation. Our proposal analyzes a novel interaction between iron deficiency and inflammation. Considering the high global prevalence of this combination of disorders in pregnant women, the subject has outstanding translational importance, and our studies could help explain commonly observed adverse outcomes. Long-term, our findings have the potential to influence the management of iron and inflammatory disorders of pregnancy.