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

ABSTRACT: Introduction: 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. Methods: 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. Results: In vivo, 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Placenta

SUBMITTER: Jun Lei

LAB HEAD: Jun Lei

PROVIDER: PXD072875 | Pride | 2026-01-12

REPOSITORIES: Pride

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			Action	DRS
	P1472_ECT60-TMT18-11.mgf	Mgf
	P1472_ECT60-TMT18-11.msf	Msf
	P1472_ECT60-TMT18-11.mzTab	Mztab
	P1472_ECT60-TMT18-11_F1.raw	Raw
	P1472_ECT60-TMT18-11_F10.raw	Raw

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Project description:Using proteomics and complexome profiling we studied longitudinal variations in the plasma proteome of two kidney transplant recipients, prior to and after their transplantation, in comparison to two healthy controls. Their post-transplant course was complicated with several bacterial infections, resulting in dramatic changes in the plasma proteome, especially in acute phase protein concentrations. As positive acute phase proteins, being elevated upon inflammation, we observed the well-known C-reactive protein (CRP) and Serum Amyloid A (SAA1 and SAA2), but also Fibrinogen (FGA, FGB and FGG), Haptoglobin (HP), Leucine-rich alpha-2-glycoprotein (LRG1), Lipopolysaccharide-binding protein (LBP), Alpha-1-antitrypsin (SERPINA1), Alpha-1-antichymotrypsin (SERPINA3), Protein S100 (S100A8, S100A9), Complement protein C4, C4b-binding protein alpha chain (C4BPA), Complement factor B (CFB) and Monocyte differentiation antigen CD14. As negative acute phase proteins, being downregulated upon inflammation, we identified the well-documented Serotransferrin (TF) and Transthyretin (TTR), but also Kallistatin (SERPINA4), Heparin cofactor 2 (SERPIND1), Inter-alpha-trypsin inhibitor heavy chain H1 and H2 (ITIH1, ITIH2). For patient P2, who showed the most severe acute phase response, we additionally performed plasma complexome profiling by SEC-LC-MS on all longitudinal samples. We observe that several plasma proteins displaying alike concentration patterns, co-elute and possibly form macromolecular complexes. These include a) FGA, FGB and FGG (naturally, b) ITIH1 and ITIH2, c) HP and Hemoglobin (HB), d) the small acute phase biomarker proteins SAA1 and SAA2 with the Apolipoproteins A-I, A-II, A-IV (APOA1, APOA2, APOA4). By complexome profiling we expose how SAA1 and SAA2 likely become incorporated into high-density lipid particles, thereby replacing partly APOA1 and APOA4. Overall, our data highlight that the combination of in-depth longitudinal plasma proteome and complexome profiling can shed further light on the correlated variations in the abundance of several plasma proteins upon inflammatory events.

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

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