Exosomal delivery of NF-κB inhibitor delays LPS-induced preterm birth and modulates fetal immune cell profile in mouse models

Accumulation of immune cells and activation of the pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is a key feature of preterm birth (PTB) pathophysiology. Reduction of the fetal inflammatory response and NF-κB activation are key strategies to minimize infection-associat...

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Bibliographic Details
Published in:Science advances 2021-01, Vol.7 (4)
Main Authors: Sheller-Miller, Samantha, Radnaa, Enkhtuya, Yoo, Jae-Kwang, Kim, Eunsoo, Choi, Kyungsun, Kim, Youngeun, Kim, Yu Na, Richardson, Lauren, Choi, Chulhee, Menon, Ramkumar
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Female
Fetus
Humans
Infant, Newborn
Inflammation - metabolism
Lipopolysaccharides - adverse effects
Mice
NF-kappa B - metabolism
Pregnancy
Premature Birth - metabolism
Uterus - metabolism
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Summary:Accumulation of immune cells and activation of the pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is a key feature of preterm birth (PTB) pathophysiology. Reduction of the fetal inflammatory response and NF-κB activation are key strategies to minimize infection-associated PTB. Therefore, we engineered extracellular vesicles (exosomes) to contain an NF-κB inhibitor, termed super-repressor (SR) IκBα. Treatment with SR exosomes (1 × 10 per intraperitoneal injection) after lipopolysaccharide (LPS) challenge on gestation day 15 (E15) prolonged gestation by over 24 hours (PTB ≤ E18.5) and reduced maternal inflammation ( ≥ 4). Furthermore, using a transgenic model in which fetal tissues express the red fluorescent protein tdTomato while maternal tissues do not, we report that LPS-induced PTB in mice is associated with influx of fetal innate immune cells, not maternal, into feto-maternal uterine tissues. SR packaged in exosomes provides a stable and specific intervention for reducing the inflammatory response associated with PTB.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abd3865