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Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability.

ABSTRACT: Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA-1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, the HPA-1, metalloproteinase 9 (MMP-9) and syndecan 1 (CD138) serum levels were all increased in dengue patients, and only NS1 and MIF showed a positive correlation with the CD138 level in severe patients. To further characterize and clarify the relationship between MIF and CD138, we used recombinant NS1 to stimulate human cells in vitro and challenge mice in vivo. Our tabulated results suggested that NS1 stimulation could induce human endothelial cells to secrete HPA-1 and immune cells to secrete MMP-9, resulting in endothelial glycocalyx degradation and hyperpermeability. Moreover, HPA-1, MMP-9, and CD138 secretion after NS1 stimulation was blocked by MIF inhibitors or antibodies both in vitro and in mice. Taken together, these results suggest that MIF directly engages in dengue NS1-induced glycocalyx degradation and that targeting MIF may represent a possible therapeutic approach for preventing dengue-induced vascular leakage.

SUBMITTER: Chen HR

PROVIDER: S-EPMC6044858 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability.

Chen Hong-Ru HR Chao Chiao-Hsuan CH Liu Ching-Chuan CC Ho Tzong-Shiann TS Tsai Huey-Pin HP Perng Guey-Chuen GC Lin Yee-Shin YS Wang Jen-Ren JR Yeh Trai-Ming TM

PLoS pathogens 20180427 4

Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA-1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, ...[more]

PMID: 29702687

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Project description:Pathological hyperpermeability is a morbidity involved in various systemic diseases, including sepsis. The endothelial glycocalyx layer (GCX) plays a key role in controlling vascular permeability and could be a useful therapeutic target. The purpose of the present study was to analyze the functional role of the GCX in vascular permeability and to elucidate its role in pathological conditions. First, male C57BL/6J wild-type mice were used as in vivo models to study the effects of sepsis and the pharmacological digestion of glycosaminoglycans (GAGs) on the GCX. Vascular permeability was evaluated using fluorescein isothiocyanate (FITC)-labeled dextran. Second, the changes in gene expression in vascular endothelial cells after GAGs digestion were compared between a control and a septic model using RNA sequencing. In the in vivo study, the glycocalyx was depleted in both the septic model and the group with pharmacological GAGs digestion. FITC-labeled dextran had leaked into the interstitium in the septic group, but not in the other groups. In the in vitro study, histamine decreased the transendothelial electrical resistance (TEER), indicating an increase in permeability. GAGs digestion alone did not change the TEER, and the effect of histamine on the TEER was not enhanced by GAGs digestion. The gene expression profiles after GAGs digestion differed from the control condition, indicating the initiation of signal transduction. In conclusion, we demonstrated that the structural barrier of the GCX does not solely determine the fluid permeability of the endothelial layer, since enzymatic depletion of the GCX did not increase the permeability. The gene expression findings suggest that the digestion of GAGs alone did not induce hyperpermeability either in vitro or in vivo, although sepsis did induce hyperpermeability. While GAGs degradation by itself does not appear to induce hyperpermeability, it may play an important role in initiating signal transductions.

Project description:BackgroundEndothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet to be elucidated whether heparanase activity plays a major role in dengue-associated plasma leakage. Moreover, the major source of heparanase secretion and activation in dengue remains elusive. Since a relatively high amount of heparanase is stored in platelets, we postulate that heparanase released by activated platelets contributes to the increased plasma heparanase activity during dengue virus infection.MethodsHeparanase activity (plasma and urine), and heparan sulfate and syndecan-1 (plasma levels) were measured in dengue patients with thrombocytopenia in acute phase (n=30), during course of disease (n=10) and in convalescent phase (n=25). Associations with clinical parameters and plasma leakage markers were explored. Platelets from healthy donors were stimulated with dengue non-structural protein-1, DENV2 virus and thrombin to evaluate heparanase release and activity ex vivo.ResultsHeparanase activity was elevated in acute dengue and normalized during convalescence. Similarly, glycocalyx components, such as heparan sulfate and syndecan-1, were increased in acute dengue and restored during convalescence. Increased heparanase activity correlated with the endothelial dysfunction markers heparan sulfate and syndecan-1, as well as clinical markers of plasma leakage such as ascites, hematocrit concentration and gall-bladder wall thickening. Notably, platelet number inversely correlated with heparanase activity. Ex vivo incubation of platelets with thrombin and live DENV2 virus, but not dengue virus-2-derived non-structural protein 1 induced heparanase release from platelets.ConclusionTaken together, our findings suggest that the increase of heparanase activity in dengue patients is associated with endothelial glycocalyx degradation and plasma leakage. Furthermore, thrombin or DENV2 activated platelets may be considered as a potential source of heparanase.

Dataset Information

Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability.

Publications

Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability.

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