Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta.

Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia.

Preeclampsia (PE) is the leading cause of maternal and fetal mortality globally and may trigger dementia later in life in mothers and their offspring. However, the etiological drivers remain elusive. Cis P-tau is an early etiological driver and blood biomarker in pre-clinical Alzheimer's and after vascular or traumatic brain injury, which can be targeted by stereo-specific antibody, with clinical trials ongoing.

Gestational Age-Dependent Regulation of Transthyretin in Mice during Pregnancy.

Our prior studies have shown that protein misfolding and aggregation in the placenta are linked to the development of preeclampsia, a severe pregnancy complication. We identified transthyretin (TTR) as a key component of the aggregated protein complex. However, the regulation of native TTR in normal pregnancy remains unclear.

The Role of Autophagy in the Female Reproduction System: For Beginners to Experts in This Field.

Autophagy is a fundamental process involved in regulating cellular homeostasis. Autophagy has been classically discovered as a cellular process that degrades cytoplasmic components non-selectively to produce energy. Over the past few decades, this process has been shown to work in energy production, as well as in the reduction of excessive proteins, damaged organelles, and membrane trafficking.

Chloroquine is a safe autophagy inhibitor for sustaining the expression of antioxidant enzymes in trophoblasts.

Inhibition of autophagy contributes to the pathophysiology of preeclampsia. Although chloroquine (CHQ) is an autophagy inhibitor, it can reduce the occurrence of preeclampsia in women with systemic lupus erythematosus. To clarify this important clinical question, this study aimed to address the safety of CHQ in trophoblast cells from the viewpoint of homeostasis, in which the anti-oxidative stress (OS) response and autophagy are involved.

Hypoxia-Reoxygenation Impairs Autophagy-Lysosomal Machinery in Primary Human Trophoblasts Mimicking Placental Pathology of Early-Onset Preeclampsia.

We have previously described that placental activation of autophagy is a central feature of normal pregnancy, whereas autophagy is impaired in preeclampsia (PE). Here, we show that hypoxia-reoxygenation (H/R) treatment dysregulates key molecules that maintain autophagy-lysosomal flux in primary human trophoblasts (PHTs). Ultrastructural analysis using transmission electron microscopy reveals a significant reduction in autophagosomes and autolysosomes in H/R-exposed PHTs.

Evidence From Human Placenta, Endoplasmic Reticulum-Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia.

Background: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several aggregated proteins in the circulation of preeclampsia patients, the most prominent of which is the serum protein TTR (transthyretin). However, the mechanisms that underlie protein aggregation remain poorly addressed.

Methods: We examined TTR aggregates in hypoxia/reoxygenation-exposed primary human trophoblasts (PHTs) and the preeclampsia placenta using complementary approaches, including a novel protein aggregate detection assay.

Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy.

Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear.

Etiological Value of Sterile Inflammation in Preeclampsia: Is It a Non-Infectious Pregnancy Complication?

Understanding of sterile inflammation and its associated biological triggers and diseases is still at the elementary stage. This becomes more warranted in cases where infections are not associated with the pathology. Detrimental effects of bacterial and viral infections on the immune responses at the maternal-fetal interface as well as pregnancy outcomes have been well documented.

Novel blood test for early biomarkers of preeclampsia and Alzheimer's disease.

A non-invasive and sensitive blood test has long been a goal for early stage disease diagnosis and treatment for Alzheimer's disease (AD) and other proteinopathy diseases. We previously reported that preeclampsia (PE), a severe pregnancy complication, is another proteinopathy disorder with impaired autophagy. We hypothesized that induced autophagy deficiency would promote accumulation of pathologic protein aggregates.

Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia.

Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival.

Molecular and immunological developments in placentas.

Cytotrophoblasts differentiate in two directions during early placentation: syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). STBs face maternal immune cells in placentas, and EVTs, which invade the decidua and uterine myometrium, face the cells in the uterus. This situation, in which trophoblasts come into contact with maternal immune cells, is known as the maternal-fetal interface.

Placental autophagy failure: A risk factor for preeclampsia.

Hypertensive disorders of pregnancy, including preeclampsia, directly affect maternal and perinatal morbidity and mortality. As the pathophysiology of preeclampsia is multi-factorial and has been studied using different approaches, we have demonstrated that impaired autophagy is an intertwined risk factor for preeclampsia. This concept has been verified in both in vitro and in vivo experiments.

Placental extracellular vesicles and pre-eclampsia.

Pre-eclampsia is a hypertensive disease of pregnancy characterized by new-onset hypertension, with either proteinuria and/or organ dysfunction. Pre-eclampsia is a leading cause of maternal morbidity and mortality; however, the underlying cellular and molecular mechanisms are not well understood. There is consensus that the underlying mechanism(s) resulting in pre-eclampsia is centered around abnormal placentation, inadequate spiral-artery remodeling, and deficiency in trophoblast invasion, resulting in impaired maternal blood flow to the placenta and a release of signals and/or inflammatory mediators into maternal circulation triggering the systemic manifestations of pre-eclampsia.

Disruption of Placental Homeostasis Leads to Preeclampsia.

Placental homeostasis is directly linked to fetal well-being and normal fetal growth. Placentas are sensitive to various environmental stressors, including hypoxia, endoplasmic reticulum stress, and oxidative stress. Once placental homeostasis is disrupted, the placenta may rebel against the mother and fetus.

Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia.

The etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE.

Pyroptosis is a critical inflammatory pathway in the placenta from early onset preeclampsia and in human trophoblasts exposed to hypoxia and endoplasmic reticulum stressors.

Systemic manifestation of preeclampsia (PE) is associated with circulating factors, including inflammatory cytokines and damage-associated molecular patterns (DAMPs), or alarmins. However, it is unclear whether the placenta directly contributes to the increased levels of these inflammatory triggers. Here, we demonstrate that pyroptosis, a unique inflammatory cell death pathway, occurs in the placenta predominantly from early onset PE, as evidenced by elevated levels of active caspase-1 and its substrate or cleaved products, gasdermin D (GSDMD), IL-1β, and IL-18.

Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts.

Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood.

Current Understanding of Autophagy in Pregnancy.

Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy.

Maternal-fetal cross talk through cell-free fetal DNA, telomere shortening, microchimerism, and inflammation.

There exists a strong correlation between unscheduled inflammation at the maternal-fetal interface and the continuum of pregnancy complications. In normal pregnancy, immunological tolerance is established to protect the semi-allogeneic fetus. There has been extensive research on how the immunity, endovascular trophoblast migration, and hormonal nexus are orchestrated during pregnancy at the maternal-fetal interface to program a normal pregnancy outcome.

Autophagy regulation in preeclampsia: Pros and cons.

Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis against stress. This process has two main functions: producing energy and quality control of intracellular proteins. During early pregnancy, extravillous trophoblasts (EVTs) invade the uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions.

Aggregated transthyretin is specifically packaged into placental nano-vesicles in preeclampsia.

In preeclampsia, the serum levels of transthyretin, a carrier protein for thyroxine, are elevated. Transthyretin isolated from preeclamptic serum is also aggregated and can induce preeclampsia-like symptoms in pregnant IL10 mice. Using western blotting, immunofluorescence, ELISA and qRT-PCR, we investigated the production of transthyretin by preeclamptic placentae and whether transthyretin is carried into the maternal circulation via placental extracellular vesicles.

NK cell-derived IL-10 is critical for DC-NK cell dialogue at the maternal-fetal interface.

DC-NK cell interactions are thought to influence the development of maternal tolerance and de novo angiogenesis during early gestation. However, it is unclear which mechanism ensures the cooperative dialogue between DC and NK cells at the feto-maternal interface. In this article, we show that uterine NK cells are the key source of IL-10 that is required to regulate DC phenotype and pregnancy success.