Regular ArticleAn innate sense of danger☆
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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-1α 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.
A key role for NLRP3 signaling in preterm labor and birth driven by the alarmin S100B
2023, Translational ResearchPreterm 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.
Roles of human trophoblasts’ pattern recognition receptors in host defense and pregnancy complications
2023, Journal of Reproductive ImmunologyThe immune system in pregnancy is able to protect pregnant mothers and fetuses from pathogenic microorganisms even while permitting the mother to tolerate the semi-allogenic fetus. Trophoblasts, which are fetal-derived placental cells, play a central role on both sides of this duality at the maternal-fetal interface. In brief, the trophoblasts express pattern recognition receptors (PRRs) and are involved in the local innate immune response in the placenta. That response eliminates pathogenic microbes but also causes tissue damage. In this review, we summarize the research findings to date regarding the roles of those human trophoblast PRRs. Multiple types of PRRs (Toll-like receptors, Nod-like receptors, and RIG-I-like receptors) are expressed in the placenta and on trophoblasts. Trophoblasts’ PRRs participate in protecting the fetus against viruses, bacteria, and parasites by triggering production of proinflammatory cytokines and chemokines in the placenta. On the negative side, PRR signaling in trophoblasts can also initiate inflammation and trophoblast cell death, which can lead to placental inflammation-associated pregnancy complications such as preeclampsia, anti-phospholipid antibody syndrome, and miscarriage. Further elucidation of these dual roles of trophoblasts’ PRRs may shed light on the mechanisms by which fetuses are protected against congenital infections and also give us a better understanding of the etiologies of pregnancy complications, which can help us prevent/reduce adverse prenatal/neonatal outcomes.
Proinflammatory changes in the maternal circulation, maternal–fetal interface, and placental transcriptome in preterm birth
2023, American Journal of Obstetrics and GynecologyPreterm birth remains a leading obstetrical complication because of the incomplete understanding of its multifaceted etiology. It is known that immune alterations toward a proinflammatory profile are observed in women with preterm birth, but therapeutic interventions are still lacking because of scarcity of evidence in the integration of maternal and placental interrelated compartments.
This study aimed to obtain an integrated view of the maternal and placental contribution to preterm birth compared with normal term pregnancies for an in-depth understanding of the immune/inflammatory involvement, intending to identify novel strategies to mitigate the negative impact of inflammation.
We prospectively recruited 79 women with preterm or term deliveries and collected placentas for RNA sequencing, histologic analyses, and to assess levels of inflammatory mediators. Blood samples were also collected to determine the circulating immune profiles by flow cytometry and to evaluate the circulating levels of inflammatory mediators.
Placental transcriptomic analyses revealed 102 differentially expressed genes upregulated in preterm birth, including known and novel targets, which were highly enriched for inflammatory biological processes according to gene ontology analyses. Analysis of maternal immune cells revealed distinct profiles in preterm births vs term births, including an increased percentage of CD3− cells and monocyte subsets and decreased CD3+ cells along with Th17 subsets of CD4+ lymphocytes. Supporting our bioinformatic findings, we found increases in proinflammatory mediators in the plasma, placenta, and fetal membranes (primarily the amnion) of women with preterm birth, such as interleukin-6 and tumor necrosis factor-α. These findings were not distinct between spontaneous and iatrogenic preterm births except at a molecular level where spontaneous preterm birth presented with an elevated inflammatory profile compared with iatrogenic preterm birth. Analysis of placental histology revealed increased structural and inflammatory lesions in preterm vs term births. We found that genes upregulated in placentas with inflammatory lesions have enrichment of proinflammatory pathways.
This work sheds light on changes within the immune system in preterm birth on multiple levels and compartments to help identify pregnancies at high risk of preterm birth and to discover novel therapeutic targets for preterm birth.
The evolving epidemiology of multiple organ failure
2023, Current Therapy of Trauma and Surgical Critical CareMultiple organ failure (MOF) emerged in the early 1970s with the advent of intensive care units (ICUs). Sepsis and trauma were recognized to be the primary inciting events. MOF was initially viewed to be “fatal expression of uncontrolled infection” caused by intra-abdominal infection. As a result, research focused on preventing IAIs as well and stress formula TPN to prevent the resulting “septic auto-cannibalism”. In the mid-1980s, it was shown that blunt trauma frequently induced a non-infectious “sepsis syndrome” phenotype. Research efforts focused on identifying the driving mechanisms. Unrecognized shock was identified and it became a common ICU practice to maximize oxygen delivery to eliminate “oxygen debt”. In the late 1980s, tremendous advances in trauma care resulted in decreased early deaths. However, an epidemic of iatrogenic abdominal compartment syndrome (ACS) emerged as a new phenotype. Simultaneously, “sepsis syndrome” was replaced by the SIRS/CARS paradigm to explain the bimodal presentation on early and late MOF. In the late 1990s, again fundamental advances in trauma care reduced early deaths, but largely eliminated ACS. In the 2000s, implementing the Glue Grant trauma and the Surviving Sepsis Campaign evidence based guidelines in surgical ICU substantially decreased ICU deaths from MOF. However, MOF had evolved into a lingering phenotype of chronic critical illness (CCI). The term persistent inflammation, immunosuppression, and catabolism syndrome (PICS) was coined to describe the new phenotype and to provide a mechanistic framework in which to study CCI in surgical ICU patients. A recently completed 5 year prospective study of surgical ICU sepsis demonstrated that while ICU deaths were surprising low, over a 1/3rd of patients progressed into CCI. Roughly, 80% of CCI patients had a poor discharge disposition suffering from severe disabilities and a 1 year mortality of 40%. Serial biomarkers out to 28 days validated the PICS–CCI paradigm.
Inflammation
2022, Encyclopedia of Infection and ImmunityUnderstanding the role of inflammation as a function of clinical disease is required for the design of treatment modalities and the development of therapeutics. Inflammation is an essential component critical for everyday health and immune homeostasis, without which the body cannot discern regular biological turnover and events from outside harmful interference. The processes involved in the inflammatory response are examined, with emphasis on defining the cellular players and chemical mediators involved. A historical definition of inflammation is provided, followed by descriptive elements of inflammatory danger signals. Cellular players involved in the inflammatory reactions are then introduced, followed by a discussion of innate and adaptive mediators. While the primary focus is to understand innate inflammation, consequences of hypersensitive inflammation are also briefly discussed. The information provides an overview of the complex processes of inflammation that form the underlying basis for unique organ-specific pathologies.
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