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STAT1-dependent signal integration between IFNγ and TLR4 in vascular cells reflect pro-atherogenic responses in human atherosclerosis.

Chmielewski S, Olejnik A, Sikorski K, Pelisek J, Błaszczyk K, Aoqui C, Nowicka H, Zernecke A, Heemann U, Wesoly J, Baumann M, Bluyssen HA - PLoS ONE (2014)

Bottom Line: The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner.Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries.Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University Poznan, Poznan, Poland.

ABSTRACT
Signal integration between IFNγ and TLRs in immune cells has been associated with the host defense against pathogens and injury, with a predominant role of STAT1. We hypothesize that STAT1-dependent transcriptional changes in vascular cells involved in cross-talk between IFNγ and TLR4, reflect pro-atherogenic responses in human atherosclerosis. Genome-wide investigation identified a set of STAT1-dependent genes that were synergistically affected by interactions between IFNγ and TLR4 in VSMCs. These included the chemokines Cxcl9, Ccl12, Ccl8, Ccrl2, Cxcl10 and Ccl5, adhesion molecules Cd40, Cd74, and antiviral and antibacterial genes Rsad2, Mx1, Oasl1, Gbp5, Nos2, Batf2 and Tnfrsf11a. Among the amplified genes was also Irf8, of which Ccl5 was subsequently identified as a new pro-inflammatory target in VSMCs and ECs. Promoter analysis predicted transcriptional cooperation between STAT1, IRF1, IRF8 and NFκB, with the novel role of IRF8 providing an additional layer to the overall complexity. The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner. Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries. Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis. Our study provides evidence to suggest that in ECs and VSMCs STAT1 orchestrates a platform for cross-talk between IFNγ and TLR4, and identifies a STAT1-dependent gene signature that reflects a pro-atherogenic state in human atherosclerosis.

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Expression of pSTAT1, CXCL9, CXCL10 in human atherosclerotic lesions in situ.Staining of the sections prepared from normal human artery exhibited no presence of pSTAT1, CXCL9, CXCL10 (A, upper panel). In contrast, all three proteins could be detected in SM-M10 positive cells in atherosclerotic plaques (A, middle panel) as well as in the endothelial cells at the lumen side (B). A representative analysis is shown of 6 human carotid atherosclerotic lesions and 4 healthy controls. Arrows represent examples of positive staining. In B arrows with asterix indicate examples of positively stained VSMCs. Scale bar = 100 µm.
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pone-0113318-g006: Expression of pSTAT1, CXCL9, CXCL10 in human atherosclerotic lesions in situ.Staining of the sections prepared from normal human artery exhibited no presence of pSTAT1, CXCL9, CXCL10 (A, upper panel). In contrast, all three proteins could be detected in SM-M10 positive cells in atherosclerotic plaques (A, middle panel) as well as in the endothelial cells at the lumen side (B). A representative analysis is shown of 6 human carotid atherosclerotic lesions and 4 healthy controls. Arrows represent examples of positive staining. In B arrows with asterix indicate examples of positively stained VSMCs. Scale bar = 100 µm.

Mentions: We performed immunohistochemistry staining for phosphorylated STAT1, CXCL9 and CXCL10 in human advanced atherosclerotic plaques of carotid arteries in comparison to healthy vessels. As can clearly be observed in Figure 6A, VSMCs in the lesion highly expressed phosphorylated STAT1 and both chemokines CXCL9 and CXCL10. In contrast, healthy vessels were negative for all three markers (Figure 6A). Moreover, ECs covering the plaque likewise showed predominant staining for phosphorylated STAT1 and CXCL9, and to a lesser extent for CXCL10 (Figure 6B). Again, healthy endothelium was negative. Staining for IRF8 was more difficult to interpret, but seemed present at low levels in SMCs (not shown).


STAT1-dependent signal integration between IFNγ and TLR4 in vascular cells reflect pro-atherogenic responses in human atherosclerosis.

Chmielewski S, Olejnik A, Sikorski K, Pelisek J, Błaszczyk K, Aoqui C, Nowicka H, Zernecke A, Heemann U, Wesoly J, Baumann M, Bluyssen HA - PLoS ONE (2014)

Expression of pSTAT1, CXCL9, CXCL10 in human atherosclerotic lesions in situ.Staining of the sections prepared from normal human artery exhibited no presence of pSTAT1, CXCL9, CXCL10 (A, upper panel). In contrast, all three proteins could be detected in SM-M10 positive cells in atherosclerotic plaques (A, middle panel) as well as in the endothelial cells at the lumen side (B). A representative analysis is shown of 6 human carotid atherosclerotic lesions and 4 healthy controls. Arrows represent examples of positive staining. In B arrows with asterix indicate examples of positively stained VSMCs. Scale bar = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257532&req=5

pone-0113318-g006: Expression of pSTAT1, CXCL9, CXCL10 in human atherosclerotic lesions in situ.Staining of the sections prepared from normal human artery exhibited no presence of pSTAT1, CXCL9, CXCL10 (A, upper panel). In contrast, all three proteins could be detected in SM-M10 positive cells in atherosclerotic plaques (A, middle panel) as well as in the endothelial cells at the lumen side (B). A representative analysis is shown of 6 human carotid atherosclerotic lesions and 4 healthy controls. Arrows represent examples of positive staining. In B arrows with asterix indicate examples of positively stained VSMCs. Scale bar = 100 µm.
Mentions: We performed immunohistochemistry staining for phosphorylated STAT1, CXCL9 and CXCL10 in human advanced atherosclerotic plaques of carotid arteries in comparison to healthy vessels. As can clearly be observed in Figure 6A, VSMCs in the lesion highly expressed phosphorylated STAT1 and both chemokines CXCL9 and CXCL10. In contrast, healthy vessels were negative for all three markers (Figure 6A). Moreover, ECs covering the plaque likewise showed predominant staining for phosphorylated STAT1 and CXCL9, and to a lesser extent for CXCL10 (Figure 6B). Again, healthy endothelium was negative. Staining for IRF8 was more difficult to interpret, but seemed present at low levels in SMCs (not shown).

Bottom Line: The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner.Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries.Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University Poznan, Poznan, Poland.

ABSTRACT
Signal integration between IFNγ and TLRs in immune cells has been associated with the host defense against pathogens and injury, with a predominant role of STAT1. We hypothesize that STAT1-dependent transcriptional changes in vascular cells involved in cross-talk between IFNγ and TLR4, reflect pro-atherogenic responses in human atherosclerosis. Genome-wide investigation identified a set of STAT1-dependent genes that were synergistically affected by interactions between IFNγ and TLR4 in VSMCs. These included the chemokines Cxcl9, Ccl12, Ccl8, Ccrl2, Cxcl10 and Ccl5, adhesion molecules Cd40, Cd74, and antiviral and antibacterial genes Rsad2, Mx1, Oasl1, Gbp5, Nos2, Batf2 and Tnfrsf11a. Among the amplified genes was also Irf8, of which Ccl5 was subsequently identified as a new pro-inflammatory target in VSMCs and ECs. Promoter analysis predicted transcriptional cooperation between STAT1, IRF1, IRF8 and NFκB, with the novel role of IRF8 providing an additional layer to the overall complexity. The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner. Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries. Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis. Our study provides evidence to suggest that in ECs and VSMCs STAT1 orchestrates a platform for cross-talk between IFNγ and TLR4, and identifies a STAT1-dependent gene signature that reflects a pro-atherogenic state in human atherosclerosis.

Show MeSH
Related in: MedlinePlus