Accumulation of γδT cells in the decidua is promoted by RANKL which upregulates ICAM-1 via NF-κB.

In brief: The mechanism underlying the accumulation of γδT cells in the decidua, which helps maintain maternal-fetal immunotolerance in early pregnancy, is unknown. This study reveals that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. Abstract: Decidual γδT (dγδT) cells help maintain maternal-fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL upregulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs), and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the number of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, an in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL overexpression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 upregulation. Taken together, our data show that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and, in turn, RSA.

Distribution, occurrence, and leachability of typical heavy metals in coal gasification slag.

Coal gasification slag (CGS) contains variable amounts of heavy metals, which can negatively impact the environment. The mineral composition, element distribution, occurrence, and leaching characteristics of heavy metals in coal gasification coarse slag (CGCS) and coal gasification fine slag (CGFS) are studied to explain the leaching behavior of heavy metals in CGS. The movable components of heavy metals in CGFS (0.06 %-63.03 %) are significantly higher than those in CGCS (0 %-18.72 %). Leaching Environmental Assessment Framework 1313 data shows that heavy metals Zn, Cr, Cd, As, Pb, Ni, and Cu exhibit high leaching rates at low pH conditions, with Zn leaching concentrations as high as 2.11 mg/L at pH 2. Zn, Cr, and As exhibit obvious amphoteric leaching characteristics, and the leaching concentration of As at high pH (1.34 mg/L) even exceeds that at low pH (1.31 mg/L). Except for Cu, all heavy metals in CGS exceed the class III groundwater standard in some cases. Therefore, evaluation is needed before resource utilization of CGS due to potential leaching of some heavy metals.

PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPß signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.

Introduction: Dysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown. Methods: First-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo. Results: The downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPß expression in uterine macrophages. Discussion: PlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPß signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages.

Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.

Innate Lymphoid Cells at the Maternal-Fetal Interface in Human Pregnancy.

Pregnancy constitutes a major challenge to the maternal immune system, which must tolerate fetal alloantigen encoded by paternal genes. In addition to their role in inducing maternal-fetal immune tolerance, accumulating evidence indicates that decidual immune cells are involved in several processes required for a successful pregnancy, including trophoblast invasion as well as tissue and spiral artery remodeling. Innate lymphoid cells (ILCs), an important branch of the innate immune system, which has expanded rapidly in recent years, are strong actors in mucosal immunity, tissue homeostasis and metabolism regulation. With the recent identification of ILCs in the human decidua, the role of ILCs at the maternal-fetal interface raises concern. Herein, we review the presence and characterization of ILCs in the human decidua, as well as their function in normal pregnancy and pathological pregnancy, including reproductive failure, preeclampsia and others.

Melatonin alleviates progression of uterine endometrial cancer by suppressing estrogen/ubiquitin C/SDHB-mediated succinate accumulation.

Succinate is an important intermediate of the tricarboxylic acid cycle. Recently discovered roles of succinate demonstrate its involvement in immunity and cancer biology; however, the precise underlying mechanisms of its involvement in these additional roles remain to be determined. In the present study, succinate dehydrogenase (SDH) B was decreased in uterine endometrial cancer cells (UECC) under negative regulation of estrogen. This decrease was the result of lower expression levels of ubiquitin C (UBC), which was associated with the activation of peroxisome proliferator-activated receptor gamma and specificity protein 1. The decreased levels of SDHB resulted in the accumulation of succinate in UECC, and thus, a decrease in the production of fumaric acid. Succinate downregulated voltage-gated potassium channel subfamily Q member 1 (KCNQ1) levels by activating serum/glucocorticoid regulated kinase 1 and promoted the growth of UECC in vitro and in vivo. Treatment with melatonin restricted estrogen/UBC/SDHB-induced succinate accumulation and upregulated expression of KCNQ1 and reduced the succinate-mediated growth of UECC in vitro and in vivo. Furthermore, overexpression of melatonin receptor 1B amplified the inhibitory effects of melatonin on succinate-mediated UECC growth. Together, the data in the present study suggest that melatonin suppresses UECC progression by inhibiting estrogen/UBC/SDHB-induced succinate accumulation. The present study provides a scientific basis for potential therapeutic strategies and targets in UEC, particularly for patients with abnormally low levels of SDHB.

Trophoblast-derived CXCL12 promotes CD56bright CD82- CD29+ NK cell enrichment in the decidua.

PROBLEM: Decidual natural killer (dNK) cells play key roles in maternal-fetal immune regulation, trophoblast invasion, and vascular remodeling, and most dNK cell populations are CD56bright CD16- NK cells. However, the enrichment and redistribution of dNK cells in the local decidua have not been clarified yet. METHOD OF STUDY: A total of 45 women with normal pregnancies and 8 unexplained recurrent spontaneous abortion (RSA) patients were included. We isolated primary human dNK (n = 53) and peripheral blood NK (pNK) cells (n = 5) from specimen and analyzed CD56, CD82, and CD29 by flow cytometry (FCM). We assessed their adhesion ability by cell counts of NK cells adhered to decidual stromal cells (DSCs) in a co-culture system. RESULTS: We found that RSA patients had more CD56dim dNK cells with lower CD82 and higher CD29 than women with normal pregnancies. There were negative correlations of CD82 to CD29 on CD56dim and CD56+ dNK cells. In normal pregnancies, dNK cells had lower CD82 and higher CD29 expression with a stronger adhesion ability than pNK cells. Blocking CD82 on dNK cells increased the adhesive ability and CD29 expression, while blocking CD29 decreased the adhesive ability. Co-culturing dNK cells with trophoblast cells decreased CD82 expression and increased the adhesive ability of dNK cells and the percentage of CD56bright NK cells, while blocking trophoblast-derived CXCL12 increased CD82 expression, decreased CD29 expression, and impaired the adhesive ability of NK cells. CONCLUSION: Trophoblast cells enhance the adhesive ability of NK cells to DSCs via the CXCL12/CD82/CD29 signaling pathway and contribute to CD56bright NK cell enrichment in the uterus.

Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-ß1-producing regulatory γδ T cells.

ABSTACT: Decidual Î³Î´Τ (dγδΤ) cells play an essential role during successful pregnancy; however, the residence and polarization of Î³Î´Τ cells in decidua remain unclear. In this study, we observed higher levels of receptor activator for nuclear factor-κ B ligand (RANKL) on decidual stromal cells (DSCs), and its receptor RANK on dÎ³Î´Τ cells in decidua from normal pregnancy compared with patients with recurrent spontaneous abortion (RSA). RANKL expressed by DSCs can induce the polarization of peripheral blood Î³Î´Τ (pγδΤ) and dÎ³Î´Τ cells to Foxp3 + Î³Î´Τ cells, and upregulate the expression of transforming growth factor (TGF)-ß1. This process is mediated through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, RANKL promotes the adhesion of dÎ³Î´Τ cells to DSCs in vitro, which is associated with the upregulation of ICAM-1 and VCAM-1 on DSCs and integrins on dÎ³Î´Τ cells. RANKL knockout leads to the decreased numbers of uterus total Î³Î´Τ cells, Foxp3+Î³Î´Τ cells and the expression of TGF-ß1, and the increased pregnancy loss in mice. These results suggest that RANKL is a pivotal regulator of maternal-fetal tolerance by triggering the polarization and residence of TGF-ß1-producing Foxp3+Î³Î´Τ cells in early pregnancy. The abnormal low level of RANKL/RANK results in pregnancy loss because of the dialogue disorder between DSCs and dÎ³Î´Τ cells. This observation provides a scientific basis on which a potential marker can be detected to early warning of pregnancy loss.

The role of indoleamine-2,3-dioxygenase in normal and pathological pregnancies.

The survival of allogeneic fetus during pregnancy contradicts the laws of immune responses. Behind this paradoxical phenomenon, the mechanism is quite complex. Indoleamine-2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism. Emerging evidence shows that IDO is expressed at the maternal-fetal interface, including trophoblast cells, decidual stroma cells, decidual immune cells (eg, natural killer cells, T cells, and macrophages), and vascular endothelial cells of decidua and chorion. Moreover, the expression and activity of IDO are different among non-pregnant, normal pregnant, and pathological pregnant conditions. IDO plays important roles in normal pregnancy through immune suppression and regulation of fetal invasion and circulation. However, the abnormal expression and dysfunction of IDO are associated with some pathological pregnancies (including recurrent spontaneous abortion, preeclampsia, preterm labor, and fetal growth restriction).

Acute uveal effusion during phacoemulsification with preoperative central serous chorioretinopathy: a case report.

BACKGROUND: We report a case of acute uveal effusion during phacoemulsification in an eye with preoperative chronic central serous chorioretinopathy (CSC). CASE PRESENTATION: A 55-year-old man with a history of chronic CSC for >18 months presented with bilateral opaque lenses. A preoperative ophthalmic examination showed suspected lenticonus and risky anatomical features, including a thick ciliary body, and anterior rotation of the ciliary process and iris root in both eyes. Optical coherence tomography (OCT) detected CSC in the left eye, but the results of fundus photography and B-scan ultrasonography were unremarkable. The anterior chamber flattened during phacoemulsification. Anterior vitrectomy was quickly performed for suspected infusion misdirection syndrome, and was followed by uneventful surgery. On postoperative day 1, fundus photography, type B ultrasound, and OCT revealed uveal exudation in the macula of the left eye. On postoperative day 50, the patient's visual acuity recovered to 20/32, and fundus photography, ultrasonography, and OCT revealed complete resolution of the uveal effusion. CONCLUSIONS: This case suggests an association between preoperative CSC and uveal effusion during surgery, because choroidal hyperperfusion and hyperpermeability were present in the patient's CSC-affected eyes.

Type II Peter's anomaly with histopathological proof: a case report.

BACKGROUND: Peter's anomaly is a rare congenital anterior segment dysgenesis with poor visual results. This case report describes a case of bilateral Type II Peter's anomaly with notable clinical and histopathological features. CASE PRESENTATION: A 7-year-old boy was admitted to our center with complaints of bilateral central opacification, photophobia and severe reduced vision since birth. He underwent phacoemulsification, intraocular lens (IOL) implantation and anterior vitrectomy on the right eye in another medical institution two years ago. Slit lamp examination revealed bilateral central corneal opacity, few strands of peripheral iris, irregular pupils and cloudy lens with central adhesion to posterior corneal surface in the left eye. Additionally, a history of premature birth and mental retardation was also noted. The patient was diagnosed with Peter's anomaly in the left eye, pseudophakia in the right eye and bilateral amblyopia. Similar surgery to the right one was performed on the left eye. A vesicle-like structure was found in the anterior chamber intraoperatively, which was composed mainly of immature lens and some corneal stroma as revealed by postoperative histopathological examinations. CONCLUSIONS: The exact mechanism of Peter's anomaly is not completely understood, however, the notable histopathological features of tissue obtained from the present case may provide evidence to the hypothesis of developmental anomalies.

New cataract markers: Mechanisms of disease.

Cataract is caused by nutritional, metabolic, environmental, and genetic factors, and is a significant cause of blindness and visual impairment. In recent years, extensive research into the human genome has revealed that numerous genetic mutations are associated with cataract. These mutations affect a variety of genes, including those encoding crystallin, membrane proteins, cytoskeletal proteins, transcription factors, and metabolism-related proteins. Elucidation of these mutations and the genetic and molecular mechanisms has helped clarify the etiology of cataract and may facilitate its early diagnosis and treatment. This review summarizes recent advances in our knowledge and potential clinical of genetic markers of cataract.

Clinical Features of Congenital and Developmental Cataract in East China: A Five-year Retrospective Review.

Congenital/developmental cataract is a significant cause of blindness in children worldwide. Full knowledge of clinical features is essential for early diagnosis and proper treatment to prevent irreversible visual impairment. We conducted a retrospective chart review on 520 congenital/developmental cataract cases based on a five-year clinical data from Eye and ENT Hospital of Fudan University, Shanghai, China. Clinical features including age at the surgery, chief complaints, interval between initial identification of cataract-related manifestations and surgery, etc. were summarized. 56.3% of children were bilateral. The age at surgery ranged from 0.25 to 17.4 years, only 9.2% receiving surgery below 1 year. Interval between initial identification of manifestations and surgery ranged from 2 days to 17 years. Concomitant congenital abnormalities were present in 67 patients, with persistent hyperplastic primary vitreous and congenital heart disease as the most frequent ocular and systemic disorders. Strabismus and nystagmus were seen in 20.6% and 11.9% of patients. In bilateral cataract patients with strabismus, axial lengths of esotropia-affected eyes were statistically shorter than exotropia-affected eyes. These findings provide information on characteristics of congenital/developmental cataract in China and may assist in achievement of comprehensive treating strategies in these cases.

ß1,6 GlcNAc branches-modified protein tyrosine phosphatase alpha enhances its stability and promotes focal adhesion formation in MCF-7 cells.

Receptor-like protein tyrosine phosphatase alpha (RPTPα or PTPα), a type I transmembrane glycoprotein with complex N-glycans, executes multifunction roles on cell behaviors. However, its effect on tumorigenesis and metastasis remains controversial. In this study, PTPα is identified as a novel substrate of N-Acetylglucosaminyltransferase V (GnT-V). Immunofluorescence results showed that addition of ß1,6 GlcNAc branches on PTPα enhanced PTPα's cytomembrane assemble in GnT-V-MCF-7 compared with Mock-MCF-7 (MCF7 cells transfected with the vector pcDNA3). Then we found the alleviating degradation of PTPα was observed in GnT-V-MCF-7 while PTPα in Mock-MCF-7 was prone to quick degradation. Increased cell-surface retention subsequently enhanced PTPα's catalytic activity on the dephosphorylation of Src kinase at Tyr529 and promoted focal adhesion formation and mature. Therefore, our findings could provide an insight into the molecular mechanism of how GnT-V promoted cell migration, suggesting that PTPα could be one of factors regulating promote migration of breast cancer cell.

N-Glycosylation at Asn 402 Stabilizes N-Cadherin and Promotes Cell-Cell Adhesion of Glioma Cells.

Cadherin is crucial for cell-cell adhesion and N-glycosylation of N-cadherin has been implicated in the process of mammary, renal, and ovarian carcinogenesis. However, whether N-glycosylation of N-cadherin plays a role in glioma remains unknown. Previous studies had indicated that N-glycosylation could occur at three asparagine residues of N-cadherin. By generating and over-expressing N-glycosylation-deficient N-cadherin mutants in the human glioma cell lines SHG66 and U87, we found that mutation of N402 but not of the other potentially N-glycosylated residues destabilized N-cadherin and led to its ubiquitylation and subsequent proteasomal degradation. Furthermore, destabilized N-cadherin inhibited cadherin-mediated cell-cell adhesion and promoted cell migration. Our findings reveal that N-glycosylation controls N-cadherin stability and plays a role in glioma migration. J. Cell. Biochem. 118: 1423-1431, 2017. © 2016 Wiley Periodicals, Inc.