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

TNF-α or VEGF-mediated NFκB activation promotes inflammation and opening up of EC junctions leading to increased vascular permeability. Increased VCAM-1 is associated with altered EC function and recruitment of immune cells. We propose (A) Inhibition of SK1. (B) Increased miRNA levels will reduce TNF-α or VEGF-mediated NFκB activation and reduce VCAM-1 expression leading to maintenance or improvement of vascular integrity.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4644833&req=5

fig1: TNF-α or VEGF-mediated NFκB activation promotes inflammation and opening up of EC junctions leading to increased vascular permeability. Increased VCAM-1 is associated with altered EC function and recruitment of immune cells. We propose (A) Inhibition of SK1. (B) Increased miRNA levels will reduce TNF-α or VEGF-mediated NFκB activation and reduce VCAM-1 expression leading to maintenance or improvement of vascular integrity.

Mentions: As stated above, growing evidence suggests a positive association between SK1 activity and TNF-α responses. Additionally, reports show that TNF-α is strongly linked to DENV disease in mice [63, 64]. TNF-α antibody can reduce the DENV-induced lethality in mice [82] and high levels of TNF-α in the circulation correlate with disease severity in humans [45, 46]. Therefore, inhibiting SK1 activity may prevent the pathogenic effects of TNF-α actions on the EC during DENV infection, as outlined in Figure 1. SK inhibitors are in development as anticancer therapeutics [83, 84] and perhaps these could be investigated for DENV treatment. Although this would require a fine therapeutic balance between inhibition of the deleterious role for SK1 in promoting inflammatory responses, whilst maintaining essential roles of SK1 in maintaining vascular integrity, the use of SK1 inhibitors has been shown to inhibit the induction of EC permeability by thrombin and neutrophils in an in vitro model and thus this selectivity of action is feasible [85]. Furthermore, recent advances in the selective targeting of inhibitors specifically to cytokine-activated EC have shown success in reducing NFκB activation in vivo [86]. This suggests that a similar approach may be possible for targeting SK1 in these cells during the activation of EC associated with DENV infection.


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)

TNF-α or VEGF-mediated NFκB activation promotes inflammation and opening up of EC junctions leading to increased vascular permeability. Increased VCAM-1 is associated with altered EC function and recruitment of immune cells. We propose (A) Inhibition of SK1. (B) Increased miRNA levels will reduce TNF-α or VEGF-mediated NFκB activation and reduce VCAM-1 expression leading to maintenance or improvement of vascular integrity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: TNF-α or VEGF-mediated NFκB activation promotes inflammation and opening up of EC junctions leading to increased vascular permeability. Increased VCAM-1 is associated with altered EC function and recruitment of immune cells. We propose (A) Inhibition of SK1. (B) Increased miRNA levels will reduce TNF-α or VEGF-mediated NFκB activation and reduce VCAM-1 expression leading to maintenance or improvement of vascular integrity.
Mentions: As stated above, growing evidence suggests a positive association between SK1 activity and TNF-α responses. Additionally, reports show that TNF-α is strongly linked to DENV disease in mice [63, 64]. TNF-α antibody can reduce the DENV-induced lethality in mice [82] and high levels of TNF-α in the circulation correlate with disease severity in humans [45, 46]. Therefore, inhibiting SK1 activity may prevent the pathogenic effects of TNF-α actions on the EC during DENV infection, as outlined in Figure 1. SK inhibitors are in development as anticancer therapeutics [83, 84] and perhaps these could be investigated for DENV treatment. Although this would require a fine therapeutic balance between inhibition of the deleterious role for SK1 in promoting inflammatory responses, whilst maintaining essential roles of SK1 in maintaining vascular integrity, the use of SK1 inhibitors has been shown to inhibit the induction of EC permeability by thrombin and neutrophils in an in vitro model and thus this selectivity of action is feasible [85]. Furthermore, recent advances in the selective targeting of inhibitors specifically to cytokine-activated EC have shown success in reducing NFκB activation in vivo [86]. This suggests that a similar approach may be possible for targeting SK1 in these cells during the activation of EC associated with DENV infection.

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