Limits...
Dengue Virus-Induced Inflammation of the Endothelium and the Potential Roles of Sphingosine Kinase-1 and MicroRNAs.

Aloia AL, Abraham AM, Bonder CS, Pitson SM, Carr JM - Mediators Inflamm. (2015)

Bottom Line: One of the main pathogenic effects of severe dengue virus (DENV) infection is a vascular leak syndrome.The cause of the vascular leakage is permeability changes in the endothelial cells lining the vasculature that are brought about by elevated vasoactive cytokine and chemokines induced following DENV infection.Furthermore, we hypothesise roles for two factors, sphingosine kinase-1 and microRNAs (miRNAs), with a focus on several candidate miRNAs, which are known to control normal vascular function and inflammatory responses.

View Article: PubMed Central - PubMed

Affiliation: Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, SA 5042, Australia.

ABSTRACT
One of the main pathogenic effects of severe dengue virus (DENV) infection is a vascular leak syndrome. There are no available antivirals or specific DENV treatments and without hospital support severe DENV infection can be life-threatening. The cause of the vascular leakage is permeability changes in the endothelial cells lining the vasculature that are brought about by elevated vasoactive cytokine and chemokines induced following DENV infection. The source of these altered cytokine and chemokines is traditionally believed to be from DENV-infected cells such as monocyte/macrophages and dendritic cells. Herein we discuss the evidence for the endothelium as an additional contributor to inflammatory and innate responses during DENV infection which may affect endothelial cell function, in particular the ability to maintain vascular integrity. Furthermore, we hypothesise roles for two factors, sphingosine kinase-1 and microRNAs (miRNAs), with a focus on several candidate miRNAs, which are known to control normal vascular function and inflammatory responses. Both of these factors may be potential therapeutic targets to regulate inflammation of the endothelium during DENV infection.

No MeSH data available.


Related in: MedlinePlus

The interaction of miR-155, miR-221/222, and miR-126 in regulation of Ets-1 driven endothelial cell inflammation. A variety of proinflammatory extracellular factors induce Ets-1 transcription which subsequently induces expression of EC proteins involved in T-cell recruitment. miR-155 and miR-221/222 act to reduce translation of Ets-1, while miR-126 acts further downstream to reduce VCAM-1 translation.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4644833&req=5

fig3: The interaction of miR-155, miR-221/222, and miR-126 in regulation of Ets-1 driven endothelial cell inflammation. A variety of proinflammatory extracellular factors induce Ets-1 transcription which subsequently induces expression of EC proteins involved in T-cell recruitment. miR-155 and miR-221/222 act to reduce translation of Ets-1, while miR-126 acts further downstream to reduce VCAM-1 translation.

Mentions: miR-126 is one of the most abundantly expressed miRNAs in EC and is known to be involved in the inflammatory response, angiogenesis, and vascular integrity [116–118]. Expression of miR-126 is regulated by the transcription factor E26 transformation-specific sequence-1 and -2 (Ets-1 and Ets-2, further discussed below) [119]. Both Ets-1 and Ets-2(−/−) and miR-126(−/−) mice show a similar phenotype of impaired vascular formation and partial lethality [117, 118, 120, 121]. miR-126 represses the translation or degrades the mRNA of three key EC genes involved in vascular integrity and inflammation: SPRED1, PI3KR2, and VCAM-1 [117, 118, 122]. SPRED1 is a negative regulator of the MAP kinase pathway and interacts with testicular protein kinase-1 (TESK-1) to prevent the phosphorylation of cofilin [117, 118, 123, 124]. Unphosphorylated cofilin leads to disrupted adherens junctions and contributes to an increase in EC permeability. Overexpression of SPRED1 or knockdown of miR-126 also decreases responsiveness to VEGF, a factor crucial in maintaining EC permeability. Likewise, PI3KR2, a negative regulator of the PI3 kinase pathway, inhibits VEGF induced vascular integrity. The roles of miR-126 in EC permeability are summarised in Figures 2 and 3. miR-126 suppresses VCAM-1 levels and therefore is important in preventing initiation of inflammation in resting EC (Figure 3) [122]. Additionally, Ets-1, a transcriptional activator of miR-126, induces VCAM-1 expression in response to proinflammatory mediators. This coalesces as a neatly regulated negative feedback process by which VCAM-1 mediated inflammation can be controlled: Ets-1 induces VCAM-1 and miR-126, with miR-126 subsequently reducing transcription of VCAM-1 [119].


Dengue Virus-Induced Inflammation of the Endothelium and the Potential Roles of Sphingosine Kinase-1 and MicroRNAs.

Aloia AL, Abraham AM, Bonder CS, Pitson SM, Carr JM - Mediators Inflamm. (2015)

The interaction of miR-155, miR-221/222, and miR-126 in regulation of Ets-1 driven endothelial cell inflammation. A variety of proinflammatory extracellular factors induce Ets-1 transcription which subsequently induces expression of EC proteins involved in T-cell recruitment. miR-155 and miR-221/222 act to reduce translation of Ets-1, while miR-126 acts further downstream to reduce VCAM-1 translation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4644833&req=5

fig3: The interaction of miR-155, miR-221/222, and miR-126 in regulation of Ets-1 driven endothelial cell inflammation. A variety of proinflammatory extracellular factors induce Ets-1 transcription which subsequently induces expression of EC proteins involved in T-cell recruitment. miR-155 and miR-221/222 act to reduce translation of Ets-1, while miR-126 acts further downstream to reduce VCAM-1 translation.
Mentions: miR-126 is one of the most abundantly expressed miRNAs in EC and is known to be involved in the inflammatory response, angiogenesis, and vascular integrity [116–118]. Expression of miR-126 is regulated by the transcription factor E26 transformation-specific sequence-1 and -2 (Ets-1 and Ets-2, further discussed below) [119]. Both Ets-1 and Ets-2(−/−) and miR-126(−/−) mice show a similar phenotype of impaired vascular formation and partial lethality [117, 118, 120, 121]. miR-126 represses the translation or degrades the mRNA of three key EC genes involved in vascular integrity and inflammation: SPRED1, PI3KR2, and VCAM-1 [117, 118, 122]. SPRED1 is a negative regulator of the MAP kinase pathway and interacts with testicular protein kinase-1 (TESK-1) to prevent the phosphorylation of cofilin [117, 118, 123, 124]. Unphosphorylated cofilin leads to disrupted adherens junctions and contributes to an increase in EC permeability. Overexpression of SPRED1 or knockdown of miR-126 also decreases responsiveness to VEGF, a factor crucial in maintaining EC permeability. Likewise, PI3KR2, a negative regulator of the PI3 kinase pathway, inhibits VEGF induced vascular integrity. The roles of miR-126 in EC permeability are summarised in Figures 2 and 3. miR-126 suppresses VCAM-1 levels and therefore is important in preventing initiation of inflammation in resting EC (Figure 3) [122]. Additionally, Ets-1, a transcriptional activator of miR-126, induces VCAM-1 expression in response to proinflammatory mediators. This coalesces as a neatly regulated negative feedback process by which VCAM-1 mediated inflammation can be controlled: Ets-1 induces VCAM-1 and miR-126, with miR-126 subsequently reducing transcription of VCAM-1 [119].

Bottom Line: One of the main pathogenic effects of severe dengue virus (DENV) infection is a vascular leak syndrome.The cause of the vascular leakage is permeability changes in the endothelial cells lining the vasculature that are brought about by elevated vasoactive cytokine and chemokines induced following DENV infection.Furthermore, we hypothesise roles for two factors, sphingosine kinase-1 and microRNAs (miRNAs), with a focus on several candidate miRNAs, which are known to control normal vascular function and inflammatory responses.

View Article: PubMed Central - PubMed

Affiliation: Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, SA 5042, Australia.

ABSTRACT
One of the main pathogenic effects of severe dengue virus (DENV) infection is a vascular leak syndrome. There are no available antivirals or specific DENV treatments and without hospital support severe DENV infection can be life-threatening. The cause of the vascular leakage is permeability changes in the endothelial cells lining the vasculature that are brought about by elevated vasoactive cytokine and chemokines induced following DENV infection. The source of these altered cytokine and chemokines is traditionally believed to be from DENV-infected cells such as monocyte/macrophages and dendritic cells. Herein we discuss the evidence for the endothelium as an additional contributor to inflammatory and innate responses during DENV infection which may affect endothelial cell function, in particular the ability to maintain vascular integrity. Furthermore, we hypothesise roles for two factors, sphingosine kinase-1 and microRNAs (miRNAs), with a focus on several candidate miRNAs, which are known to control normal vascular function and inflammatory responses. Both of these factors may be potential therapeutic targets to regulate inflammation of the endothelium during DENV infection.

No MeSH data available.


Related in: MedlinePlus