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Browsing by Author "Miller, Derek"

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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.
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.
Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes
(2023) Farias-Jofre, Marcelo; Romero, Roberto; Galaz, Jose; Xu, Yi; Miller, Derek; Garcia-Flores, Valeria; Arenas-Hernandez, Marcia; Winters, Andrew D.; Berkowitz, Bruce A.; Podolsky, Robert H.; Shen, Yimin; Kanninen, Tomi; Panaitescu, Bogdan; Glazier, Catherine R.; Pique-Regi, Roger; Theis, Kevin R.; Gomez-Lopez, Nardhy
Background Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.Methods Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1 alpha in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1 alpha. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.Findings IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1 alpha. Intra-amniotic injection of IL-1 alpha resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1 alpha exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1 alpha-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL -6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.Interpretation IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.
Cellular immune responses in amniotic fluid of women with a sonographic short cervix
(2020) Galaz, Jose; Romero, Roberto; Xu, Yi; Miller, Derek; Levenson, Dustyn; Para, Robert; Varrey, Aneesha; Hsu, Richard; Tong, Anna; Hassan, Sonia S.; Hsu, Chaur-Dong; Gomez-Lopez, Nardhy
Objectives: A sonographic short cervix is one of the strongest predictors of preterm delivery. However, the cellular immune composition of amniotic fluid in women with a short cervix has not yet been described. Herein, we determined cellular and soluble immune responses in amniotic fluid from pregnant women with a mid-trimester asymptomatic short cervix.
Cellular immune responses in amniotic fluid of women with preterm clinical chorioamnionitis
(2020) Galaz, Jose; Romero, Roberto; Xu, Yi; Miller, Derek; Slutsky, Rebecca; Levenson, Dustyn; Hsu, Chaur-Dong; Gomez-Lopez, Nardhy
Objective Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Some preterm births are associated with clinical chorioamnionitis; yet, this condition has been poorly investigated. Herein, we characterized the amniotic fluid cellular immune responses in women with preterm clinical chorioamnionitis. Methods and subjects Amniotic fluid samples were obtained from women with preterm clinical chorioamnionitis and a positive or negative microbiological culture (n = 17). The cellular composition of amniotic fluid was evaluated using fluorescence microscopy, scanning and transmission electron microscopy, and flow cytometry. Women without preterm clinical chorioamnionitis were also examined (n = 10). Results Amniotic fluid from women with preterm clinical chorioamnionitis and a positive culture had: (1) abundant neutrophils associated with viable and non-viable bacteria, (2) neutrophils performing phagocytosis, (3) neutrophils forming NETs, (4) increased numbers of neutrophils, monocytes/macrophages, and CD4+ T cells, and (5) high expression of IL-1 beta by neutrophils and monocytes/macrophages. Amniotic fluid from women with preterm clinical chorioamnionitis and proven infection tended to have fewer monocytes/macrophages and CD4+ T cells compared to those without chorioamnionitis. Conclusion We provide the first morphologic and phenotypic characterization of the cellular immune responses in the amniotic cavity of women with preterm clinical chorioamnionitis, a condition associated with adverse neonatal outcomes.
Clinical chorioamnionitis at term IX : in vivo evidence of intra-amniotic inflammasome activation
(2019) Gomez-López, Nardhy; Romero, Roberto; Maymon, Ely; Kusanovic, Juan Pedro; Panaitescu, Bogdan; Miller, Derek; Pacora, Percy; Tarca, Adi L.; Motomura, Kenichiro; Erez, Offer; Jung, Eunjung J.; Hassan, Sonia S.; Hsu, Chaur Dong
Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing
(2024) Garcia-Flores, Valeria; Romero, Roberto; Tarca, Adi L.; Peyvandipour, Azam; Xu, Yi; Galaz, Jose; Miller, Derek; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Berry, Stanley M.; Awonuga, Awoniyi O.; Bryant, David R.; Pique-Regi, Roger; Gomez-Lopez, Nardhy
Labor is a complex physiological process requiring a well-orchestrated dialogue between the mother and fetus. However, the cellular contributions and communications that facilitate maternal-fetal cross-talk in labor have not been fully elucidated. Here, single-cell RNA sequencing (scRNA-seq) was applied to decipher maternal-fetal signaling in the human placenta during term labor. First, a single-cell atlas of the human placenta was established, demonstrating that maternal and fetal cell types underwent changes in transcriptomic activity during labor. Cell types most affected by labor were fetal stromal and maternal decidual cells in the chorioamniotic membranes (CAMs) and maternal and fetal myeloid cells in the placenta. Cell-cell interaction analyses showed that CAM and placental cell types participated in labor-driven maternal and fetal signaling, including the collagen, C-X-C motif ligand (CXCL), tumor necrosis factor (TNF), galectin, and interleukin-6 (IL-6) pathways. Integration of scRNA-seq data with publicly available bulk transcriptomic data showed that placenta-derived scRNA-seq signatures could be monitored in the maternal circulation throughout gestation and in labor. Moreover, comparative analysis revealed that placenta-derived signatures in term labor were mirrored by those in spontaneous preterm labor and birth. Furthermore, we demonstrated that early in gestation, labor-specific, placenta-derived signatures could be detected in the circulation of women destined to undergo spontaneous preterm birth, with either intact or prelabor ruptured membranes. Collectively, our findings provide insight into the maternal-fetal cross-talk of human parturition and suggest that placenta-derived single-cell signatures can aid in the development of noninvasive biomarkers for the prediction of preterm birth.
Defining a role for Interferon Epsilon in normal and complicated pregnancies
(2022) Miller, Derek; Romero, Roberto; Kacerovsky, Marian; Musilova, Ivana; Galaz, Jose; Garcia-Flores, Valeria; Xu, Yi; Pusod, Errile; Demery-Poulos, Catherine; Gutierrez-Contreras, Pedro; Ning Liu, Tzu; Jung, Eunjung; Theis, Kevin R.; Coleman, Lanetta A.; Gomez-Lopez, Nardhy
Interferon epsilon (IFNe) is a recently described cytokine that is constitutively expressed in the female repro-ductive tract. However, the role of this hormonally regulated cytokine during human pregnancy is poorly un-derstood. Moreover, whether IFNe participates in host immune response against bacteria-driven intra-amniotic infection or cervical human papillomavirus infection during pregnancy is unknown. Herein, using a unique set of human samples derived from multiple study cohorts, we aimed to uncover the role of IFNe in normal and complicated pregnancies. We showed that IFNe is expressed in the myometrium, cervix, and chorioamniotic membranes, and may therefore represent a constitutive element of host defense mechanisms in these tissues during pregnancy. The expression of IFNe in the myometrium and cervix appeared greater in late gestation than in mid-pregnancy, but did not seem to be impacted by labor. Notably, concentrations of IFNe in amniotic fluid, but not cervical fluid, were increased in a subset of women undergoing spontaneous preterm labor with intra-amniotic infection, indicating that IFNe could participate in anti-microbial responses in the amniotic cavity. However, stimulation with Ureaplasma parvum and/or lipopolysaccharide did not enhance IFNE expression by amnion epithelial or cervical cells in vitro, implicating alternative sources of this cytokine during intra-amniotic or cervical infection, respectively. Collectively, our results represent the first characterization of IFNe expression by human reproductive and gestational tissues during normal pregnancy and suggest a role for this cytokine in intra-amniotic infection leading to preterm birth.
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.
Exhausted and Senescent T Cells at the Maternal-Fetal Interface in Preterm and Term Labor
(2019) Slutsky, Rebecca; Romero, Roberto; Xu, Yi; Galaz, Jose; Miller, Derek; Done, Bogdan; Tarca, Adi L.; Gregor, Sabrina; Hassan, Sonia S.; Leng, Yaozhu; Gomez-Lopez, Nardhy
Successful pregnancy requires a tightly-regulated equilibrium of immune cell interactions at the maternal-fetal interface (i.e., the decidual tissues), which plays a central role in the inflammatory process of labor. Most of the innate immune cells in this compartment have been well characterized; however, adaptive immune cells are still under investigation. Herein, we performed immunophenotyping of the decidua basalis and decidua parietalis to determine whether exhausted and senescent T cells are present at the maternal-fetal interface and whether the presence of pathological (i.e., preterm) or physiological (i.e., term) labor and/or placental inflammation alter such adaptive immune cells. In addition, decidual exhausted T cells were sorted to test their functional status. We found that (1) exhausted and senescent T cells were present at the maternal-fetal interface and predominantly expressed an effector memory phenotype, (2) exhausted CD4(+) T cells increased in the decidua parietalis as gestational age progressed, (3) exhausted CD4(+) and CD8(+) T cells decreased in the decidua basalis of women who underwent labor at term compared to those without labor, (4) exhausted CD4(+) T cells declined with the presence of placental inflammation in the decidua basalis of women with preterm labor, (5) exhausted CD8(+) T cells decreased with the presence of placental inflammation in the decidua basalis of women who underwent labor at term, (6) both senescent CD4(+) and CD8(+) T cells declined with the presence of placental inflammation in the decidua basalis of women who underwent preterm labor, and (7) decidual exhausted T cells produced IFN and TNF upon in vitro stimulation. Collectively, these findings indicate that exhausted and senescent T cells are present at the human maternal-fetal interface and undergo alterations in a subset of women either with labor at term or preterm labor and placental inflammation. Importantly, decidual T cell function can be restored upon stimulation.
Fetal and maternal NLRP3 signaling is required for preterm labor and birth
(AMER SOC CLINICAL INVESTIGATION INC, 2022) Motomura, Kenichiro; Romero, Roberto; Galaz, Jose; Tao, Li; Garcia-Flores, Valeria; Xu, Yi; Done, Bogdan; Arenas-Hernandez, Marcia; Miller, Derek; Gutierrez-Contreras, Pedro; Farias-Jofre, Marcelo; Aras, Siddhesh; Grossman, Lawrence, I; Tarca, Adi L.; Gomez-Lopez, Nardhy
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and-sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.
Host-microbiome interactions in distinct subsets of preterm labor and birth
(2023) Galaz, Jose; Romero, Roberto; Greenberg, Jonathan M.; Theis, Kevin R.; Arenas-Hernandez, Marcia; Xu, Yi; Farias-Jofre, Marcelo; Miller, Derek; Kanninen, Tomi; Garcia-Flores, Valeria; Gomez-Lopez, Nardhy
Preterm birth, the leading cause of perinatal morbidity, often follows premature labor, a syndrome whose prevention remains a challenge. To better understand the relationship between premature labor and host-microbiome interactions, we conducted a mechanistic investigation using three preterm birth models. We report that intra-amniotic delivery of LPS triggers inflammatory responses in the amniotic cavity and cervico-vaginal microenvironment, causing vaginal microbiome changes and signs of active labor. Intra-amniotic IL-1 alpha delivery causes a moderate inflammatory response in the amniotic cavity but increasing inflammation in the cervico-vaginal space, leading to vaginal microbiome disruption and signs of active labor. Conversely, progesterone action blockade by RU-486 triggers local immune responses accompanying signs of active labor without altering the vaginal microbiome. Preterm labor facilitates ascension of cervico-vaginal bacteria into the amniotic cavity, regardless of stimulus. This study provides compelling mechanistic insights into the dynamic host-microbiome interactions within the cervico-vaginal microenvironment that accompany premature labor and birth.
Innate lymphoid cells at the human maternal-fetal interface in spontaneous preterm labor
(WILEY, 2018) Xu, Yi; Romero, Roberto; Miller, Derek; Silva, Pablo; Panaitescu, Bogdan; Theis, Kevin R.; Arif, Afrah; Hassan, Sonia S.; Gomez Lopez, Nardhy
Problem: Pathological inflammation is causally linked to preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Our aims were to investigate whether (i) the newly described family of innate lymphoid cells (ILCs) was present at the human maternal-fetal interface and (ii) ILC inflammatory subsets were associated with the pathological process of preterm labor.
Microbial burden and inflammasome activation in amniotic fluid of patients with preterm prelabor rupture of membranes
(2020) Theis, Kevin R.; Romero, Roberto; Motomura, Kenichiro; Galaz, Jose; Winters, Andrew D.; Pacora, Percy; Miller, Derek; Slutsky, Rebecca; Florova, Violetta; Levenson, Dustyn; Para, Robert; Varrey, Aneesha; Kacerovsky, Marian; Hsu, Chaur-Dong; Gomez-Lopez, Nardhy
Background: Intra-amniotic inflammation, which is associated with adverse pregnancy outcomes, can occur in the presence or absence of detectable microorganisms, and involves activation of the inflammasome. lntra-amniotic inflammasome activation has been reported in clinical chorioamnionitis at term and preterm labor with intact membranes, but it has not yet been investigated in women with preterm prelabor rupture of membranes (preterm PROM) in the presence/absence of detectable microorganisms. The aim of this study was to determine whether, among women with preterm PROM, there is an association between detectable microorganisms in amniotic fluid and intra-amniotic inflammation, and whether intra-amniotic inflammasome activation correlates with microbial burden.
Pregnancy imparts distinct systemic adaptive immune function
(WILEY, 2022) Demery-Poulos, Catherine; Romero, Roberto; Xu, Yi; Arenas-Hernandez, Marcia; Miller, Derek; Tao, Li; Galaz, Jose; Farias-Jofre, Marcelo; Bhatti, Gaurav; Garcia-Flores, Valeria; Seyerle, Megan; Tarca, Adi L.; Gomez-Lopez, Nardhy
Problem Pregnancy represents a state of systemic immune activation that is primarily driven by alterations in circulating innate immune cells. Recent studies have suggested that cellular adaptive immune components, T cells and B cells, also undergo changes throughout gestation. However, the phenotypes and functions of such adaptive immune cells are poorly understood. Herein, we utilized high-dimensional flow cytometry and functional assays to characterize T-cell and B-cell responses in pregnant and non-pregnant women. Methods Peripheral blood mononuclear cells from pregnant (n = 20) and non-pregnant (n = 25) women were used for phenotyping of T-cell and B-cell subsets. T-cell proliferation and B-cell activation were assessed by flow cytometry after in vitro stimulation, and lymphocyte cytotoxicity was evaluated by using a cell-based assay. Statistical comparisons were performed with linear mixed-effects models. Results Pregnancy was associated with modestly enhanced basal activation of peripheral CD4(+) T cells. Both CD4(+) and CD8(+) T cells from pregnant women showed increased activation-induced proliferation; yet, a reduced proportion of these cells expressed activation markers compared to non-pregnant women. There were no differences in peripheral lymphocyte cytotoxicity between study groups. A greater proportion of B cells from pregnant women displayed memory-like and activated phenotypes, and such cells exhibited higher activation following stimulation. Conclusion Maternal circulating T cells and B cells display distinct responses during pregnancy. The former may reflect the unique capacity of T cells to respond to potential threats without undergoing aberrant activation, thereby preventing systemic inflammatory responses that can lead to adverse perinatal consequences.
Pregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma
(2023) Gomez-Lopez, Nardhy; Romero, Roberto; Escobar, Maria Fernanda; Carvajal, Javier Andres; Echavarria, Maria Paula; Albornoz, Ludwig L.; Nasner, Daniela; Miller, Derek; Gallo, Dahiana M.; Galaz, Jose; Arenas-Hernandez, Marcia; Bhatti, Gaurav; Done, Bogdan; Zambrano, Maria Andrea; Ramos, Isabella; Fernandez, Paula Andrea; Posada, Leandro; Chaiworapongsa, Tinnakorn; Jung, Eunjung; Garcia-Flores, Valeria; Suksai, Manaphat; Gotsch, Francesca; Bosco, Mariachiara; Than, Nandor Gabor; Tarca, Adi L.
Gomez-Lopez et al. profile the plasma proteome of pregnant and non-pregnant COVID-19 patients and controls. Shared and pregnancy-specific proteomic changes are identified in COVID-19 patients compared to controls, with the proteome accurately identifying COVID-19 patients, even when asymptomatic.
Single-Cell Immunobiology of the Maternal-Fetal Interface
(2022) Miller, Derek; Garcia-Flores, Valeria; Romero, Roberto; Galaz, Jose; Pique-Regi, Roger; Gomez-Lopez, Nardhy
Pregnancy success requires constant dialogue between the mother and developing conceptus. Such crosstalk is facil-itated through complex interactions between maternal and fetal cells at distinct tissue sites, collectively termed the "maternal -fetal interface." The emergence of single-cell technologies has enabled a deeper understanding of the unique processes taking place at the maternal -fetal interface as well as the discovery of novel pathways and immune and nonimmune cell types. Single-cell approaches have also been applied to decipher the cellular dynamics through-out pregnancy, in parturition, and in obstetrical syndromes such as recurrent spontaneous abortion, preeclampsia, and preterm labor. Furthermore, single-cell technologies have been used during the recent COVID-19 pandemic to eval-uate placental viral cell entry and the impact of SARS-CoV-2 infection on maternal and fetal immunity. In this brief review, we summarize the current knowledge of cellular immunobiology in pregnancy and its complica-tions that has been generated through single-cell investi-gations of the maternal -fetal interface. The Journal of Immunology, 2022, 209: 1450-1464.
The effects of progesterone on immune cellular function at the maternal-fetal interface and in maternal circulation
(2023) Motomura, Kenichiro; Miller, Derek; Galaz, Jose; Liu, Tzu Ning; Romero, Roberto; Gomez-Lopez, Nardhy
Progesterone is a sex steroid hormone that plays a critical role in the establishment and maintenance of pregnancy. This hormone drives numerous maternal physiological adaptations to ensure the continuation of pregnancy and to facilitate fetal growth, including broad and potent modulation of the maternal immune system to promote maternal-fetal tolerance. In this brief review, we provide an overview of the immunomodulatory functions of progesterone in the decidua, placenta, myometrium, and maternal circulation during pregnancy. Specifically, we summarize current evidence of the regulated functions of innate and adaptive immune cells induced by progesterone and its downstream effector molecules in these compartments, including observations in human pregnancy and in animal models. Our review highlights the gaps in knowledge of interactions between progesterone and maternal cellular immunity that may direct future research.
The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies
(WILEY, 2018) Gomez Lopez, Nardhy; Romero, Roberto; Xu, Yi; Miller, Derek; Leng, Yaozhu; Panaitescu, Bogdan; Silva, Pablo; Faro, Jonathan; Alhousseini, Ali; Gill, Navleen; Hassan, Sonia S.; Hsu, Chaur Dong
ProblemThe immune cellular composition of amniotic fluid is poorly understood. Herein, we determined: 1) the immunophenotype of amniotic fluid immune cells during the second and third trimester in the absence of intra-amniotic infection/inflammation; 2) whether amniotic fluid T cells and ILCs display different phenotypical characteristics to that of peripheral cells; and 3) whether the amniotic fluid immune cells are altered in women with intra-amniotic infection/inflammation.
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.

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