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Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention.

ABSTRACT: Preterm birth (PTB) is a syndrome with many origins. Among them, infection or inflammation are major risk factors for PTB; however, local defense mechanisms to mount anti-inflammatory responses against inflammation-induced PTB are poorly understood. Here, we show that endothelial TLR4 in the decidual bed is critical for sensing inflammation during pregnancy because mice with endothelial Tlr4 deletion are resistant to lipopolysaccharide (LPS)-induced PTB. Under inflammatory conditions, IL-6 is readily expressed in decidual endothelial cells with signal transducer and activator of transcription 3 (Stat3) phosphorylation in perivascular stromal cells, which then regulates expression of anti-inflammatory IL-10. Our observation that administration of an IL-10 neutralizing antibody predisposing mice to PTB shows IL-10's anti-inflammatory role to prevent PTB. We show that the integration of endothelial and perivascular stromal signaling can determine pregnancy outcomes. These findings highlight a role for endothelial TLR4 in inflammation-induced PTB and may offer a potential therapeutic target to prevent PTB.

SUBMITTER: Deng W

PROVIDER: S-EPMC6554729 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention.

Deng Wenbo W Yuan Jia J Cha Jeeyeon J Sun Xiaofei X Bartos Amanda A Yagita Hideo H Hirota Yasushi Y Dey Sudhansu K SK

Cell reports 20190501 6

Preterm birth (PTB) is a syndrome with many origins. Among them, infection or inflammation are major risk factors for PTB; however, local defense mechanisms to mount anti-inflammatory responses against inflammation-induced PTB are poorly understood. Here, we show that endothelial TLR4 in the decidual bed is critical for sensing inflammation during pregnancy because mice with endothelial Tlr4 deletion are resistant to lipopolysaccharide (LPS)-induced PTB. Under inflammatory conditions, IL-6 is re ...[more]

PMID: 31067461

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Project description:Prematurity is the foremost cause of death in children under 5 years of age. Genetics contributes to 25-40% of all preterm births (PTB) yet we still need to identify specific targets for intervention based on genetic pathways. This study involved the effect of region-specific non-synonymous variations and their transcript level mutational impact on protein functioning and stability by various in-silico tools. This investigation identifies potential therapeutic targets to manage the challenge of PTB, corresponding protein cavities and explores their binding interactions with intervening compounds. We searched 20 genes coding 55 PTB proteins from NCBI. Single Nucleotide Polymorphisms (SNPs) of concerned genes were extracted from ENSEMBL, and filtration of exonic variants (non-synonymous) was performed. Several in-silico downstream protein functional effect prediction tools were used to identify damaging variants. Rare coding variants were selected with an allele frequency of ≤1% in 1KGD, further supported by South Asian ALFA frequencies and GTEx gene/tissue expression database. CNN1, COL24A1, IQGAP2 and SLIT2 were identified with 7 rare pathogenic variants found in 17 transcript sequences. The functional impact analyses of rs532147352 (R>H) of CNN1 computed through PhD-SNP, PROVEAN, SNP&GO, PMut and MutPred2 algorithms showed impending deleterious effects, and the presence of this pathogenic mutation in CNN1 resulted in large decrease in protein structural stability (ΔΔG (kcal/mol). After structural protein identification, homology modelling of CNN1, which has been previously reported as a biomarker for the prediction of PTB, was performed, followed by the stereochemical quality checks of the 3D model. Blind docking approach were used to search the binding cavities and molecular interactions with progesterone, ranked with energetic estimations. Molecular interactions of CNN1 with progesterone were investigated through LigPlot 2D. Further, molecular docking experimentation of CNN1 showed the significant interactions at S102, L105, A106, K123, Y124 with five selected PTB-drugs, Allylestrenol (-7.56 kcal/mol), Hydroxyprogesterone caproate (-8.19 kcal/mol), Retosiban (-9.43 kcal/mol), Ritodrine (-7.39 kcal/mol) and Terbutaline (-6.87 kcal/mol). Calponin-1 gene and its molecular interaction analysis could serve as an intervention target for the prevention of PTB.

Project description:Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL.

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Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention.

Publications

Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention.

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