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

Hong Ru Chen, Chiao Hsuan Chao, Ching Chuan Liu, Tzong Shiann Ho, Huey Pin Tsai, Guey Chuen Perng, Yee Shin Lin, Jen Ren Wang, Trai Ming Yeh

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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.

Original languageEnglish
Article numbere1007033
JournalPLoS pathogens
Volume14
Issue number4
DOIs
Publication statusPublished - 2018 Apr

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Macrophage Migration-Inhibitory Factors
Glycocalyx
Dengue
Metalloproteases
Proteins
Blood Vessels
Endothelial Cells
Syndecan-1
Severe Dengue
Dengue Virus
Recombinant Proteins
heparanase
Antibodies
Serum

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

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title = "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.",
author = "Chen, {Hong Ru} and Chao, {Chiao Hsuan} and Liu, {Ching Chuan} and Ho, {Tzong Shiann} and Tsai, {Huey Pin} and Perng, {Guey Chuen} and Lin, {Yee Shin} and Wang, {Jen Ren} and Yeh, {Trai Ming}",
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AU - Chen, Hong Ru

AU - Chao, Chiao Hsuan

AU - Liu, Ching Chuan

AU - Ho, Tzong Shiann

AU - Tsai, Huey Pin

AU - Perng, Guey Chuen

AU - Lin, Yee Shin

AU - Wang, Jen Ren

AU - Yeh, Trai Ming

PY - 2018/4

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