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Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Apr 12; Vol. 119 (15), pp. e2113310119. Date of Electronic Publication: 2022 Apr 04. - Publication Year :
- 2022
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Abstract
- Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although long-term phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic–polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood–brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte–endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders.
- Subjects :
- Animals
Celecoxib pharmacology
Cyclooxygenase 2 Inhibitors pharmacology
Female
Gene Deletion
Mice
Poly I-C immunology
Pregnancy
Blood-Brain Barrier abnormalities
Blood-Brain Barrier physiopathology
Cyclooxygenase 2 genetics
Cyclooxygenase 2 metabolism
Encephalitis immunology
Maternal-Fetal Exchange immunology
Microglia enzymology
Prenatal Exposure Delayed Effects immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 119
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 35377817
- Full Text :
- https://doi.org/10.1073/pnas.2113310119