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.

Matrix metalloproteinase 9 facilitates Zika virus invasion of the testis by modulating the integrity of the blood-testis barrier

“…West Nile virus, which has high tropism to the brain, can induce MMP9 expression to facilitate viral entry into the brain [34]. MMP9 is also associated with endothelial glycocalyx degradation caused by dengue virus NS1 [43].…”

Coagulopathy in COVID‐19

“…Dengue fever virus, a family of flavivirus, is known to damage the glycocalyx that leads to the increase of vascular permeability. Chen et al 42 demonstrated the Dengue virus stimulates endothelial cells to secrete glycocalyx degradation factor heparanase and modulate immune cells to secrete matrix metalloproteinase. It still remains to be clarified but similar mechanisms may also exist in COVID‐19.…”

The detection of anti-dengue virus IgM in urine in participants enrolled in an acute febrile illness study in Puerto Rico

“…Compared to IgA, IgM is a large pentamer (molecular radius 120 A˚) that is only able to pass the glomerular filtration barrier through large defects and shunts, and therefore detecting IgM in urine may indicate dysfunction of the glomerular filtration barrier [12]. Recent studies have suggested that the mechanism of vascular leakage observed in severe dengue cases is due to the disruption of the endothelial glycocalyx layer (EGL) by dengue non-structural protein 1 (NS1) [28,29]. In fact, a clinical study by Suwarto et al, found that two of the four components of EGL were elevated in the serum of severe dengue patients [30].…”