Adverse Interaction Between Iron Deficiency and Inflammation in Pregnancy

怀孕期间充足的铁供应对胎儿发育和孕产妇健康至关重要。缺铁及其最常见的表现，贫血，在怀孕期间非常普遍，可能对母亲和胎儿产生不良影响。怀孕期间的全身性母体炎症也很常见，并且要么是由感染（细菌，病毒，寄生虫）引起，要么伴随慢性疾病，包括肥胖症，糖尿病和自身免疫性疾病。与炎症妊娠相关的不良结局包括自然流产、早产、宫内生长受限、胎儿死亡、严重发育异常和后代的自闭症行为。我们在小鼠中的初步研究表明，母体缺铁和炎症之间存在令人惊讶的协同不良相互作用，导致胚胎毒性，这在单独的条件下都没有观察到。与铁状态正常的母鼠相比，铁缺乏的母鼠在LPS注射引起的急性母体炎症中胚胎异常的频率显著更高。我们的目标是定义这种协同作用的基本机制：目标1。确定铁缺乏对母体、胎盘和胚胎炎症的影响。使用我们的LPS引发炎症的小鼠模型，我们将检查妊娠期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。目标2.基于人类和小鼠胎盘TNFR 1和TFR 1之间的强相关性，我们假设细胞铁状态调节TNFR 1水平。我们将确定特定的胎盘细胞类型，增加TNFR 1在铁缺乏的反应，并检查候选人的机制调节TNFR 1。.目标3。确定TNF途径在体内不良协同作用中的作用-我们的初步数据表明TNFα-TNFR途径介导铁缺乏炎症妊娠的不良结局。我们将使用内皮细胞或滋养层特异性TNFR 1缺陷的小鼠来确定TNF途径是否是急性炎症模型中不良协同作用所必需的。目标4。确定铁缺乏对胎盘细胞转录组的影响。我们将补充我们的候选人驱动的方法与无偏见的单细胞RNAseq对小鼠胎盘从铁缺乏和铁充满妊娠治疗LPS获得详细的洞察如何铁缺乏改变胎盘细胞群以及它们的转录活性响应炎症。我们的提案分析了缺铁和炎症之间的新相互作用。考虑到这种疾病在孕妇中的高全球患病率，该主题具有突出的翻译重要性，我们的研究可以帮助解释常见的不良后果。从长远来看，我们的研究结果有可能影响妊娠期铁和炎症性疾病的管理。

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.