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Specific Inflammatory Stimuli Lead to Distinct Platelet Responses in Mice and Humans.

Beaulieu LM, Clancy L, Tanriverdi K, Benjamin EJ, Kramer CD, Weinberg EO, He X, Mekasha S, Mick E, Ingalls RR, Genco CA, Freedman JE - PLoS ONE (2015)

Bottom Line: At week 9, these cells individually localized to the spleen, while Western diet resulted in increased platelet-neutrophil aggregates in the spleen only.Results were reinforced in platelets obtained from participants of the FHS.Using both human studies and animal models, results demonstrate that variable sources of inflammatory stimuli have the ability to influence the platelet phenotype in distinct ways, indicative of the diverse function of platelets in thrombosis, hemostasis, and immunity.

View Article: PubMed Central - PubMed

Affiliation: University of Massachusetts Medical School, Department of Medicine, Division of Cardiovascular Medicine, Worcester, MA, United States of America.

ABSTRACT

Introduction: Diverse and multi-factorial processes contribute to the progression of cardiovascular disease. These processes affect cells involved in the development of this disease in varying ways, ultimately leading to atherothrombosis. The goal of our study was to compare the differential effects of specific stimuli--two bacterial infections and a Western diet--on platelet responses in ApoE-/- mice, specifically examining inflammatory function and gene expression. Results from murine studies were verified using platelets from participants of the Framingham Heart Study (FHS; n = 1819 participants).

Methods: Blood and spleen samples were collected at weeks 1 and 9 from ApoE-/- mice infected with Porphyromonas gingivalis or Chlamydia pneumoniae and from mice fed a Western diet for 9 weeks. Transcripts based on data from a Western diet in ApoE-/- mice were measured in platelet samples from FHS using high throughput qRT-PCR.

Results: At week 1, both bacterial infections increased circulating platelet-neutrophil aggregates. At week 9, these cells individually localized to the spleen, while Western diet resulted in increased platelet-neutrophil aggregates in the spleen only. Microarray analysis of platelet RNA from infected or Western diet-fed mice at week 1 and 9 showed differential profiles. Genes, such as Serpina1a, Ttr, Fgg, Rpl21, and Alb, were uniquely affected by infection and diet. Results were reinforced in platelets obtained from participants of the FHS.

Conclusion: Using both human studies and animal models, results demonstrate that variable sources of inflammatory stimuli have the ability to influence the platelet phenotype in distinct ways, indicative of the diverse function of platelets in thrombosis, hemostasis, and immunity.

No MeSH data available.


Related in: MedlinePlus

Comparison of genes affected by both bacterial infections at week 1 and week 9.Heatmap shows the transcripts identified through microarray as upregulated or downregulated 2-fold or more with either P. gingivalis (Pg) or C. pneumoniae (Cp) infection compared to Untreated Control in the ApoE-/- mice at week 1 and 9. Each condition represents RNA from 3 mice pooled.
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pone.0131688.g008: Comparison of genes affected by both bacterial infections at week 1 and week 9.Heatmap shows the transcripts identified through microarray as upregulated or downregulated 2-fold or more with either P. gingivalis (Pg) or C. pneumoniae (Cp) infection compared to Untreated Control in the ApoE-/- mice at week 1 and 9. Each condition represents RNA from 3 mice pooled.

Mentions: At week 9, following P. gingivalis and C. pneumoniae infections, before overt plaque formation had yet to occur in the aorta, alterations in both platelet transcripts and inflammatory function are still occurring. Although not directly measured in our study, previous work by our group and others have shown that each bacterium is still present in the systems of these mice. An increase in circulating P. gingivalis-specific IgG has been detected through 13 weeks post infection [46] and by 24 weeks, this bacterium is identified in aorta, heart, and liver tissue [47]. As for C. pneumoniae, there is a measurable serum IgG level up to 16 weeks, with bacteria detected in the lungs, aorta, heart, and spleen [48]. Overall, both bacteria upregulated fewer genes at the later timepoint compared that observed at week 1 (Fig 8). Infection with C. pneumoniae resulted in more downregulation in gene expression, which was further supported by GSEA, showing significant negative enrichment in gene sets. Unlike with C. pneumoniae, P. gingivalis infection alterations in gene transcript changes were diminished at week 9. It is hypothesized that over the course of the infection, megakaryocytes are slowly returning to baseline in terms of the types of RNA produced, with fewer genes and gene groups being altered. Further, changes in transcripts are also reflective of platelet function. Platelet-neutrophil aggregates are no longer in circulation at week 9. The cells were individually present in the spleens obtained from these mice. It is possible that we no longer see these cells as aggregates even in the spleens because the interaction between the platelets and neutrophils is transient, a brief interaction that results in activation of either/both cells and transfer of information on the current environment. With more platelets in the spleen, it is expected that there would be a decrease in circulating platelet levels. Instead, the platelet concentrations stay steady if not increase. This data suggest megakaryocytes are still responding to the infection, directly or indirectly.


Specific Inflammatory Stimuli Lead to Distinct Platelet Responses in Mice and Humans.

Beaulieu LM, Clancy L, Tanriverdi K, Benjamin EJ, Kramer CD, Weinberg EO, He X, Mekasha S, Mick E, Ingalls RR, Genco CA, Freedman JE - PLoS ONE (2015)

Comparison of genes affected by both bacterial infections at week 1 and week 9.Heatmap shows the transcripts identified through microarray as upregulated or downregulated 2-fold or more with either P. gingivalis (Pg) or C. pneumoniae (Cp) infection compared to Untreated Control in the ApoE-/- mice at week 1 and 9. Each condition represents RNA from 3 mice pooled.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493099&req=5

pone.0131688.g008: Comparison of genes affected by both bacterial infections at week 1 and week 9.Heatmap shows the transcripts identified through microarray as upregulated or downregulated 2-fold or more with either P. gingivalis (Pg) or C. pneumoniae (Cp) infection compared to Untreated Control in the ApoE-/- mice at week 1 and 9. Each condition represents RNA from 3 mice pooled.
Mentions: At week 9, following P. gingivalis and C. pneumoniae infections, before overt plaque formation had yet to occur in the aorta, alterations in both platelet transcripts and inflammatory function are still occurring. Although not directly measured in our study, previous work by our group and others have shown that each bacterium is still present in the systems of these mice. An increase in circulating P. gingivalis-specific IgG has been detected through 13 weeks post infection [46] and by 24 weeks, this bacterium is identified in aorta, heart, and liver tissue [47]. As for C. pneumoniae, there is a measurable serum IgG level up to 16 weeks, with bacteria detected in the lungs, aorta, heart, and spleen [48]. Overall, both bacteria upregulated fewer genes at the later timepoint compared that observed at week 1 (Fig 8). Infection with C. pneumoniae resulted in more downregulation in gene expression, which was further supported by GSEA, showing significant negative enrichment in gene sets. Unlike with C. pneumoniae, P. gingivalis infection alterations in gene transcript changes were diminished at week 9. It is hypothesized that over the course of the infection, megakaryocytes are slowly returning to baseline in terms of the types of RNA produced, with fewer genes and gene groups being altered. Further, changes in transcripts are also reflective of platelet function. Platelet-neutrophil aggregates are no longer in circulation at week 9. The cells were individually present in the spleens obtained from these mice. It is possible that we no longer see these cells as aggregates even in the spleens because the interaction between the platelets and neutrophils is transient, a brief interaction that results in activation of either/both cells and transfer of information on the current environment. With more platelets in the spleen, it is expected that there would be a decrease in circulating platelet levels. Instead, the platelet concentrations stay steady if not increase. This data suggest megakaryocytes are still responding to the infection, directly or indirectly.

Bottom Line: At week 9, these cells individually localized to the spleen, while Western diet resulted in increased platelet-neutrophil aggregates in the spleen only.Results were reinforced in platelets obtained from participants of the FHS.Using both human studies and animal models, results demonstrate that variable sources of inflammatory stimuli have the ability to influence the platelet phenotype in distinct ways, indicative of the diverse function of platelets in thrombosis, hemostasis, and immunity.

View Article: PubMed Central - PubMed

Affiliation: University of Massachusetts Medical School, Department of Medicine, Division of Cardiovascular Medicine, Worcester, MA, United States of America.

ABSTRACT

Introduction: Diverse and multi-factorial processes contribute to the progression of cardiovascular disease. These processes affect cells involved in the development of this disease in varying ways, ultimately leading to atherothrombosis. The goal of our study was to compare the differential effects of specific stimuli--two bacterial infections and a Western diet--on platelet responses in ApoE-/- mice, specifically examining inflammatory function and gene expression. Results from murine studies were verified using platelets from participants of the Framingham Heart Study (FHS; n = 1819 participants).

Methods: Blood and spleen samples were collected at weeks 1 and 9 from ApoE-/- mice infected with Porphyromonas gingivalis or Chlamydia pneumoniae and from mice fed a Western diet for 9 weeks. Transcripts based on data from a Western diet in ApoE-/- mice were measured in platelet samples from FHS using high throughput qRT-PCR.

Results: At week 1, both bacterial infections increased circulating platelet-neutrophil aggregates. At week 9, these cells individually localized to the spleen, while Western diet resulted in increased platelet-neutrophil aggregates in the spleen only. Microarray analysis of platelet RNA from infected or Western diet-fed mice at week 1 and 9 showed differential profiles. Genes, such as Serpina1a, Ttr, Fgg, Rpl21, and Alb, were uniquely affected by infection and diet. Results were reinforced in platelets obtained from participants of the FHS.

Conclusion: Using both human studies and animal models, results demonstrate that variable sources of inflammatory stimuli have the ability to influence the platelet phenotype in distinct ways, indicative of the diverse function of platelets in thrombosis, hemostasis, and immunity.

No MeSH data available.


Related in: MedlinePlus