Targeting SAA expression via siRNA mitigates preterm birth induced by maternal inflammation

TL;DR

Targeting SAA2 with siRNA reduces preterm birth caused by maternal inflammation, improving fetal outcomes.

Contribution

The study identifies SAA2 as a key inflammatory mediator in preterm birth and shows that siRNA targeting SAA2 is a potential therapeutic strategy.

Findings

SAA2 is primarily induced in placental trophoblast and endothelial compartments during inflammation.

Maternal administration of siSaa2 improved preterm birth rates, placental morphology, and fetal brain development.

SAA1 and SAA2 show distinct expression patterns in mouse and human placentas.

Abstract

Placental inflammation is a major contributor to preterm birth (PTB), and there are currently few targeted strategies to prevent PTB and its associated adverse neonatal outcomes. Serum amyloid A (SAA), particularly the isoforms SAA1 and SAA2, are well-recognized inflammatory markers, but their functional roles in placental inflammation remain poorly defined.

Using a translational mouse model of sub-chronic maternal inflammation, we investigated the immune mechanisms and therapeutic potential of siRNA-mediated targeting of Saa2 (siSaa2). Placental expression patterns of SAA2 were examined in vivo, and macrophage responses to extracellular SAA2 were modeled in vitro using RAW264.7 cells to assess downstream P2X7R-dependent signaling and functional outcomes.

SAA2 is primarily induced in placental trophoblast and endothelial compartments during inflammation, where it acts as an extracellular inflammatory mediator. In vitro, we model macrophage responses to extracellular SAA2 using RAW264.7 cells to examine downstream P2X7R-dependent signaling and functional outcomes. Maternal administration of siSaa2 improved PTB rates, placental morphology and fetal brain development. Additionally, SAA1 and SAA2 exhibited distinct expression patterns in the mouse and human placenta.

These findings identify placental SAA2 as a key inflammatory mediator in inflammation-associated PTB and demonstrate that targeted silencing of Saa2 represents a potential therapeutic strategy to mitigate placental injury and adverse fetal outcomes.

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