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

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.

Figure 1

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.

Figure 2

Roles of miR-126, miR-155, miR-221, and miR-222 in endothelial cell inflammation and maintenance of vascular integrity. (a) miR-126 regulates EC permeability through inhibition of PI3K and MAPK signaling pathways. miR-126 regulation of SPRED1 also indirectly regulates phosphorylation of cofilin and protein involved in maintenance of EC junctions. (b) Increased miR-126 levels result in a decrease in VCAM-1 levels, providing an anti-inflammatory effect. (c) miR-155 inhibits eNOS synthesis and thereby regulates EC permeability. Additionally, miR-155 inhibits Angiotensin-1 Receptor (AT1R) signaling, decreasing the expression of proinflammatory factors in EC. (d) HIV protein Tat can reduce transcription of miR-221 and miR-222, releasing their blockade on ICAM-1 translation and resulting in an inflammatory response.

Figure 3

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.