Browsing by Author "Liu, Zhenjie"

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    A key role for NLRP3 signaling in preterm labor and birth driven by the alarmin S100B
    (2023) Galaz, Jose; Motomura, Kenichiro; Romero, Roberto; Liu, Zhenjie; Garcia-Flores, Valeria; Tao, Li; Xu, Yi; Done, Bogdan; Arenas-Hernandez, Marcia; Kanninen, Tomi; Farias-Jofre, Marcelo; Miller, Derek; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Preterm birth remains the leading cause of neonatal morbidity and mortality worldwide. A substantial number of spontaneous preterm births occur in the context of sterile intra-amniotic inflammation, a condition that has been mechanistically proven to be triggered by alarmins. However, sterile intra-amniotic inflammation still lacks treatment. The NLRP3 inflammasome has been implicated in sterile intra-amniotic inflammation; yet, its underlying mechanisms, as well as the maternal and fetal contributions to this signaling pathway, are unclear. Herein, by utilizing a translational and clinically relevant model of alarmin-induced preterm labor and birth in Nlrp3-/- mice, we investigated the role of NLRP3 signaling by using imaging and molecular biology approaches. Nlrp3 deficiency abrogated preterm birth and the resulting neonatal mortality induced by the alarmin S100B by impeding the premature activation of the common pathway of labor as well as by dampening intra-amniotic and fetal inflammation. Moreover, Nlrp3 deficiency altered leukocyte infiltration and functionality in the uterus and decidua. Last, embryo transfer revealed that maternal and fetal Nlrp3 signaling contribute to alarmin-induced preterm birth and neonatal mortality, further strengthening the concept that both individuals participate in the complex process of preterm parturition. These findings provide novel insights into sterile intra-amniotic inflammation, a common etiology of preterm labor and birth, suggesting that the adverse perinatal outcomes resulting from prematurity can be prevented by targeting NLRP3 signaling.
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    A single-cell atlas of murine reproductive tissues during preterm labor
    (2023) Garcia-Flores, Valeria; Romero, Roberto; Peyvandipour, Azam; Galaz, Jose; Pusod, Errile; Panaitescu, Bogdan; Miller, Derek; Xu, Yi; Tao, Li; Liu, Zhenjie; Tarca, Adi L.; Pique-Regi, Roger; Gomez-Lopez, Nardhy
    Preterm birth, the leading cause of perinatal morbidity and mortality worldwide, frequently results from the syndrome of preterm labor. The best-established causal link to preterm labor is intra-amniotic infection, which involves premature activation of the parturition cascade in the reproductive tissues. Herein, we utilize single-cell RNA sequencing (scRNA-seq) to generate a single-cell atlas of the murine uterus, decidua, and cervix in a model of infection-induced preterm labor. We show that preterm labor affects the transcriptomic profiles of specific immune and non-immune cell subsets. Shared and tissue-specific gene expression sig-natures are identified among affected cells. Determination of intercellular communications implicates spe-cific cell types in preterm labor-associated signaling pathways across tissues. In silico comparison of murine and human uterine cell-cell interactions reveals conserved signaling pathways implicated in labor. Thus, our scRNA-seq data provide insights into the preterm labor-driven cellular landscape and communications in reproductive tissues.
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    Clarithromycin prevents preterm birth and neonatal mortality by dampening alarmin-induced maternal–fetal infammation in mice
    (2022) Galaz, José; Romero, Roberto; Arenas-Hernandez, Marcia; Farías Jofré, Marcelo Enrique; Motomura, Kenichiro; Liu, Zhenjie; Kawahara, Naoki; Demery-Poulos, Catherine; Liu, Tzu N.; Padron, Justin; Panaitescu, Bogdan; Gomez-Lopez, Nardhy
    Background: One of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses. Methods: Pregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7–8 dams each). Results: Clarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen. Conclusions: Clarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention.
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    Differential immunophenotype of circulating monocytes from pregnant women in response to viral ligands
    (2023) Farías Jofré, Marcelo Enrique; Romero, Roberto; Xu, Yi; Levenson, Dustyn; Tao, Li; Kanninen, Tomi; Galaz, Jose; Arenas-Hernandez, Marcia; Liu, Zhenjie; Miller, Derek; Bhatti, Gaurav; Seyerle, Megan; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Background Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women. Methods Peripheral blood was collected from third-trimester pregnant (n = 20) or non-pregnant (n = 20, controls) women. Peripheral blood mononuclear cells were isolated and exposed to R848 (TLR7/TLR8 agonist), Gardiquimod (TLR7 agonist), Poly(I:C) (HMW) VacciGrade™ (TLR3 agonist), Poly(I:C) (HMW) LyoVec™ (RIG-I/MDA-5 agonist), or ODN2216 (TLR9 agonist) for 24 h. Cells and supernatants were collected for monocyte phenotyping and immunoassays to detect specific interferons, respectively. Results The proportions of classical (CD14hiCD16−), intermediate (CD14hiCD16+), non-classical (CD14loCD16+), and CD14loCD16− monocytes were differentially affected between pregnant and non-pregnant women in response to TLR3 stimulation. The proportions of pregnancy-derived monocytes expressing adhesion molecules (Basigin and PSGL-1) or the chemokine receptors CCR5 and CCR2 were diminished in response to TLR7/TLR8 stimulation, while the proportions of CCR5− monocytes were increased. Such differences were found to be primarily driven by TLR8 signaling, rather than TLR7. Moreover, the proportions of monocytes expressing the chemokine receptor CXCR1 were increased during pregnancy in response to poly(I:C) stimulation through TLR3, but not RIG-I/MDA-5. By contrast, pregnancy-specific changes in the monocyte response to TLR9 stimulation were not observed. Notably, the soluble interferon response to viral stimulation by mononuclear cells was not diminished in pregnancy. Conclusions Our data provide insight into the differential responsiveness of pregnancy-derived monocytes to ssRNA and dsRNA, mainly driven by TLR8 and membrane-bound TLR3, which may help to explain the increased susceptibility of pregnant women to adverse outcomes resulting from viral infection as observed during recent and historic pandemics.
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    Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation
    (SPRINGER BASEL AG, 2022) Farias-Jofre, Marcelo; Romero, Roberto; Galaz, Jose; Xu, Yi; Tao, Li; Demery-Poulos, Catherine; Arenas-Hernandez, Marcia; Bhatti, Gaurav; Liu, Zhenjie; Kawahara, Naoki; Kanninen, Tomi; Shaffer, Zachary; Chaiworapongsa, Tinnakorn; Theis, Kevin R.; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Objective To comprehensively characterize monocyte and neutrophil responses to E. coli and its product [lipopolysaccharide (LPS) or endotoxin] in vitro during pregnancy.
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    Thymic stromal lymphopoietin participates in the host response to intra-amniotic inflammation leading to preterm labor and birth
    (2023) Kanninen, Tomi; Tao, Li; Romero, Roberto; Xu, Yi; -Hernandez, Marcia Arenas; Galaz, Jose; Liu, Zhenjie; Miller, Derek; Levenson, Dustyn; Greenberg, Jonathan M.; Panzer, Jonathan; Padron, Justin; Theis, Kevin R.; Gomez-Lopez, Nardhy
    The aim of this study was to establish the role of thymic stromal lymphopoietin (TSLP) in the intra-amniotic host response of women with spontaneous preterm labor (sPTL) and birth. Amniotic fluid and chorioamniotic membranes (CAM) were collected from women with sPTL who delivered at term (n = 30) or preterm without intra-amniotic inflammation (n = 34), with sterile intra-amniotic inflammation (SIAI, n = 27), or with intra-amniotic infection (IAI, n = 17). Amnion epithelial cells (AEC), Ureaplasma parvum, and Sneathia spp. were also utilized. The expression of TSLP, TSLPR, and IL-7R & alpha; was evaluated in amniotic fluid or CAM by RT-qPCR and/or immunoassays. AEC co-cultured with Ureaplasma parvum or Sneathia spp. were evaluated for TSLP expression by immunofluorescence and/or RT-qPCR. Our data show that TSLP was elevated in amniotic fluid of women with SIAI or IAI and expressed by the CAM. TSLPR and IL-7R & alpha; had detectable gene and protein expression in the CAM; yet, CRLF2 was specifically elevated with IAI. While TSLP localized to all layers of the CAM and increased with SIAI or IAI, TSLPR and IL-7R & alpha; were minimal and became most apparent with IAI. Co -culture experiments indicated that Ureaplasma parvum and Sneathia spp. differentially upregulated TSLP expression in AEC. Together, these findings indicate that TSLP is a central component of the intra-amniotic host response during sPTL.