Roles of Interleukin-17 in Endothelial Cells Endothelial cell (EC) activation and inflammation significantly contribute to vascular inflammation. In addition to being stimulated by proinflammatory/proatherogenic risk factors such as hyperlipidemia, ECs are also the target of proinflammatory cytokines. Since 2003, a new lineage of CD4+RORt+ (retinoid-related orphan receptor) T cells has been defined by its production of proinflammatory cytokine interleukin-17 (IL-17) and hence named T-helper 17 (Th17) cells. These cells are found to play an essential role in promoting autoimmune diseases and inflammation. However, an important question of whether molecular signaling pathway of IL-17 plays a critical role in EC activation remains to be answered. Therefore, the goal of this proposal is to examine a central hypothesis that IL-17, induced by hyperlipidemia, plays a critical role in EC activation. The publications from our labs and others' as well as our preliminary data support this hypothesis: (i) IL-17 receptor A (IL-17RA) is expressed in aortic ECs. High levels of IL-17 receptor C (IL-17RC) expression are observed in ECs, suggesting the functional receptor complex IL-17RA/C is expressed in ECs and is able to initiate signaling in response to IL-17 stimulation; (ii) IL-17 is upregulated in human aortic ECs exposed to disturbed blood flow, an EC activation condition, suggesting that ECs can be further stimulated by IL-17 via an autocrine mechanism; (iii) Plasma IL-17 level and Th17 cells are elevated in apolipoprotein E deficient (ApoE-/- ) atherogenic mice, suggesting that hyperlipidemia makes more IL-17 available to stimulate ECs; and (iv) Inhibition of IL-17 suppresses inflammation. Inhibition of IL-17 with antibodies attenuates vascular inflammation in ApoE-/- mice, suggesting that IL-17 plays a critical role in vascular inflammation. We have a long standing interest in studying immune regulation of endothelial activation and vascular inflammation. Therefore, we have the expertise to complete this project. This goal will be pursued through the execution of the following specific aims: (1) To determine whether IL-17 signaling pathway is upregulated in aortic ECs in ApoE-/- mice; (2) To determine whether IL-17-induced human EC activation is mechanistically dependent on its upregulation of proinflammatory cytokines and chemokines; (3) To determine whether IL-17 gene depletion inhibits EC activation in IL-17-/-/ApoE-/- mice. This project is significant since success of this project may lead to future development of new therapeutics for treating EC activation/inflammation.

Public Health Relevance

There is increasing evidence that vascular endothelial cell (ECs) activation and inflammation significantly contribute to the development of vascular inflammation. However, the importance of newly characterized cytokine interleukin-17 (IL-17) signaling plays a critical role in initiating EC activation and inflammation remains poorly defined. The proposed studies will provide better understanding whether the elucidation of IL-17 molecular signaling in EC activation and inflammation can lead to the development of new therapeutics for treating vascular cell inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108910-05
Application #
8856318
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hasan, Ahmed AK
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Cueto, Ramon; Zhang, Lixiao; Shan, Hui Min et al. (2018) Identification of homocysteine-suppressive mitochondrial ETC complex genes and tissue expression profile - Novel hypothesis establishment. Redox Biol 17:70-88
Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2017) Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells. Can J Physiol Pharmacol 95:247-252
Virtue, Anthony; Johnson, Candice; Lopez-PastraƱa, Jahaira et al. (2017) MicroRNA-155 Deficiency Leads to Decreased Atherosclerosis, Increased White Adipose Tissue Obesity, and Non-alcoholic Fatty Liver Disease: A NOVEL MOUSE MODEL OF OBESITY PARADOX. J Biol Chem 292:1267-1287
Li, Xinyuan; Fang, Pu; Yang, William Y et al. (2017) IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases. Cytokine :
Xu, Yanjie; Xia, Jixiang; Liu, Suxuan et al. (2017) Endocytosis and membrane receptor internalization: implication of F-BAR protein Carom. Front Biosci (Landmark Ed) 22:1439-1457
Dai, Jin; Fang, Pu; Saredy, Jason et al. (2017) Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation. J Hematol Oncol 10:141
Yang, Jiyeon; Fang, Pu; Yu, Daohai et al. (2016) Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation. Circ Res 119:1226-1241
Ferrer, Lucas M; Monroy, Alexandra M; Lopez-Pastrana, Jahaira et al. (2016) Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. J Cardiovasc Transl Res 9:135-44
Li, Xinyuan; Fang, Pu; Li, Yafeng et al. (2016) Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation. Arterioscler Thromb Vasc Biol 36:1090-100
Mai, Jietang; Nanayakkara, Gayani; Lopez-Pastrana, Jahaira et al. (2016) Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway. J Biol Chem 291:4939-54

Showing the most recent 10 out of 45 publications