Maternal-Fetal Inflammation in the Placenta and the Developmental Origins of Health and Disease (2020)

Affiliations

• 1 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
• 2 Department of Nutritional Sciences, College of Health and Human Development, Penn State University, University Park, PA, United States.
• 3 Section of Allergy and Immunology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital and Northwestern University, Chicago, IL, United States.

Abstract

Events in fetal life impact long-term health outcomes. The placenta is the first organ to form and is the site of juxtaposition between the maternal and fetal circulations.

Most diseases of pregnancy are caused by, impact, or are reflected in the placenta.

The purpose of this review is to describe the main inflammatory processes in the placenta, discuss their immunology, and relate their short- and long-term disease associations.

Acute placental inflammation (API), including maternal and fetal inflammatory responses corresponds to the clinical diagnosis of chorioamnionitis and is associated with respiratory and neurodevelopmental diseases.

The chronic placental inflammatory pathologies (CPI), include chronic villitis of unknown etiology, chronic deciduitis, chronic chorionitis, eosinophilic T-cell vasculitis, and chronic histiocytic intervillositis.

These diseases are less-well studied, but have complex immunology and show mechanistic impacts on the fetal immune system.

Overall, much work remains to be done in describing the long-term impacts of placental inflammation on offspring health.

Maternal immune activation in mice disrupts proteostasis in the fetal brain (2021)

[Proteostasis:

"A typical mammalian cell contains up to 20,000 types of protein, which must be continually regulated and maintained.

"The homeostasis of these proteins, also referred to as 'proteostasis', is a complex pathway that functions to maintain all of the proteins within and around a cell."
----News Medical Life Sciences]

ISR = Integrated Stress Response]

Affiliations

• 1 Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
• 2 Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
• 3 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
• 4 Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
• 5 Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
• 6 The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
• 7 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
• 8 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
• 9 Degenerative Disease Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
• 10 Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
• 11 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Jun_Huh@hms.harvard.edu.
• 12 Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
  

Abstract

Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon.

Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling.

We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis.

Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring.

Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.