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Cells
Volume 11
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10.3390/cells11152288
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Article

Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice

by
Chinchu Jagadan Ushakumari
1,2,
Qiong L. Zhou
1,2,
Yu-Hua Wang
1,2,
Sijia Na
1,2,
Michael C. Rigor
2,
Cindy Y. Zhou
2,
Max K. Kroll
2,
Benjamin D. Lin
2 and
Zhen Y. Jiang
1,2,*
1
Department of Pharmacology & Experimental Therapeutics, School of Medicine, Boston University, Boston, MA 02118, USA
2
Whitaker Cardiovascular Institute, School of Medicine, Boston University, Boston, MA 02118, USA
*
Author to whom correspondence should be addressed.
Cells 2022, 11(15), 2288; https://doi.org/10.3390/cells11152288
Submission received: 25 April 2022 / Revised: 27 June 2022 / Accepted: 21 July 2022 / Published: 25 July 2022
(This article belongs to the Special Issue Novel Mechanisms Linking Metabolic Disorders and Cardiovascular Diseases)
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Abstract

Neutrophil elastase (NE) plays a pivotal role in inflammation. However, the mechanism underlying NE-mediated inflammation in obesity remains unclear. Here, we report that NE activates protease-activated receptor-2 (PAR2), stimulates actin filament (F-actin) formation, decreases intercellular junction molecule VE-cadherin expression, and increases the permeability of human arterial endothelial cells (hECs). NE also prompts degradation of VE-cadherin and its binding proteins p120- and β-catenins via MG132-sensitive proteasomes. NE stimulates phosphorylation of myosin light-chain (MLC) and its regulator myosin phosphatase target subunit-1 (MYPT1), a target of Rho kinase (ROCK). Inhibitors of PAR2 and ROCK prohibit NE-induced F-actin formation, MLC phosphorylation, and VE-cadherin reduction in hECs, and impede monocyte transmigration through hEC monolayer pretreated with either neutrophils or NE. Further, administration of an NE inhibitor GW311616A significantly attenuates vascular leakage, leukocyte infiltration, and the expression of proinflammatory cytokines in the white adipose tissue from high-fat diet (HFD)-induced obese mice. Likewise, NE-deficient mice are resistant to HFD-induced vascular leakage in the heart. Together, NE regulates actomyosin cytoskeleton activity and VE-cadherin expression by activating PAR2 signaling in the endothelial cells, leading to increased vascular permeability and leukocyte extravasation. Hence, inhibition of NE is a potential approach to mitigate vascular injury and leukocyte infiltration in obesity-related systemic inflammation.
Keywords: neutrophil elastase; vascular endothelial injury; obesity; neutrophils; systemic inflammation neutrophil elastase; vascular endothelial injury; obesity; neutrophils; systemic inflammation

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MDPI and ACS Style

Ushakumari, C.J.; Zhou, Q.L.; Wang, Y.-H.; Na, S.; Rigor, M.C.; Zhou, C.Y.; Kroll, M.K.; Lin, B.D.; Jiang, Z.Y. Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice. Cells 2022, 11, 2288. https://doi.org/10.3390/cells11152288

AMA Style

Ushakumari CJ, Zhou QL, Wang Y-H, Na S, Rigor MC, Zhou CY, Kroll MK, Lin BD, Jiang ZY. Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice. Cells. 2022; 11(15):2288. https://doi.org/10.3390/cells11152288

Chicago/Turabian Style

Ushakumari, Chinchu Jagadan, Qiong L. Zhou, Yu-Hua Wang, Sijia Na, Michael C. Rigor, Cindy Y. Zhou, Max K. Kroll, Benjamin D. Lin, and Zhen Y. Jiang. 2022. "Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice" Cells 11, no. 15: 2288. https://doi.org/10.3390/cells11152288

APA Style

Ushakumari, C. J., Zhou, Q. L., Wang, Y.-H., Na, S., Rigor, M. C., Zhou, C. Y., Kroll, M. K., Lin, B. D., & Jiang, Z. Y. (2022). Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice. Cells, 11(15), 2288. https://doi.org/10.3390/cells11152288

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