Non-resolving chronic inflammation due to defective homeostatic resolution underlies the pathogenesis of atherosclerosis, a significant cardiovascular complication that imposes enormous health and economic tolls. Studies from the PI?s group and others indicate that the lack of effective homeostatic negative regulators may underlie the run-away inflammation and the pathogenesis of chronic atherosclerosis. The PI?s group has identified that IRAK-M (interleukin-1 receptor associated kinase M) is one of the key negative regulators of monocyte inflammation. At the molecular level, the PI observed that IRAK-M may selectively suppress inflammatory activation of monocytes through suppressing key inflammatory transcription factors such as NF?B and IRF5. At the sub-cellular level, the PI discovered that IRAK-M may maintain and restore cellular homeostasis through facilitating the proper completion of autophagy. At the tissue and pathophysiological level, the PI reported that IRAK-M deficient mice are prone to develop aggravated atherosclerosis, due to enhanced recruitment of low-grade inflammatory monocytes to the aortic plaque. The levels of monocyte IRAK-M are significantly reduced in mice under low-grade inflammatory conditions. The long-term goal is to define novel therapeutic targets for maintaining a proper balance of immune environment and treating atherosclerosis associated with chronic low-grade inflammation. Based on these novel observations, the current objective is to define molecular and cellular mechanisms by which IRAK-M modulates the inflammatory polarization of monocytes during the pathogenesis of atherosclerosis. The central hypothesis is that IRAK-M deficiency may polarize a non-resolving pro-inflammatory monocyte state through affecting autophagy completion and inflammatory signaling exacerbation conducive to the pathogenesis of atherosclerosis. To test this hypothesis, the PI plans to perform the following integrated studies.
Aim 1 will test the hypothesis that IRAK-M may maintain monocyte homeostasis through negatively regulating TRAF6-p62 mediated inflammatory signaling pathways.
Aim 2 will test the hypothesis that IRAK-M may maintain monocyte homeostasis through facilitating autophagy completion.
Aim 3 will test the hypothesis that monocyte polarization due to IRAK-M deficiency plays a key role during the exacerbation of atherosclerosis. Completion of this project will define novel molecular and cellular mechanisms responsible for the defective inflammation resolution in exacerbated atherosclerosis, and facilitate the development of therapeutic strategies in treating atherosclerosis associated with low-grade inflammation.

Public Health Relevance

The lack of inflammatory resolution due to the disruption of homeostatic modulators such as IRAK-M plays a key role in the pathogenesis of atherosclerosis. The goal of this project is to define novel cellular and molecular mechanisms responsible for the polarization of low-grade inflammation due to IRAK-M deficiency during atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL115835-06
Application #
9612651
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Liu, Lijuan
Project Start
2012-07-13
Project End
2022-04-30
Budget Start
2018-07-01
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Weston, Bronson R; Li, Liwu; Tyson, John J (2018) Mathematical Analysis of Cytokine-Induced Differentiation of Granulocyte-Monocyte Progenitor Cells. Front Immunol 9:2048
Rahtes, Allison; Geng, Shuo; Lee, Christina et al. (2018) Cellular and molecular mechanisms involved in the resolution of innate leukocyte inflammation. J Leukoc Biol 104:535-541
Kowalski, Elizabeth; Geng, Shuo; Rathes, Allison et al. (2018) Toll-interacting protein differentially modulates HIF1? and STAT5-mediated genes in fibroblasts. J Biol Chem 293:12239-12247
Lee, Christina; Geng, Shuo; Zhang, Yao et al. (2017) Programming and memory dynamics of innate leukocytes during tissue homeostasis and inflammation. J Leukoc Biol 102:719-726
Chen, Keqiang; Yuan, Ruoxi; Zhang, Yao et al. (2017) Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy. J Am Heart Assoc 6:
Rothschild, Daniel E; Zhang, Yao; Diao, Na et al. (2017) Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M. EBioMedicine 15:36-47
Chen, Keqiang; Yuan, Ruoxi; Geng, Shuo et al. (2017) Toll-interacting protein deficiency promotes neurodegeneration via impeding autophagy completion in high-fat diet-fed ApoE-/- mouse model. Brain Behav Immun 59:200-210
Geng, Shuo; Chen, Keqiang; Yuan, Ruoxi et al. (2016) The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis. Nat Commun 7:13436
Guo, Honghui; Diao, Na; Yuan, Ruoxi et al. (2016) Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet-Fed Mice. J Immunol 196:2300-2308
Yuan, Ruoxi; Li, Liwu (2016) Dynamic modulation of innate immunity programming and memory. Sci China Life Sci 59:38-43

Showing the most recent 10 out of 21 publications