# Modulation of innate immune cellular homeostasis and inflammation resolution

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $402,500

## Abstract

Project summary
 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 NFκB
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.

## Key facts

- **NIH application ID:** 10150529
- **Project number:** 5R01HL115835-09
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** LIWU LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2012-07-13 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150529

## Citation

> US National Institutes of Health, RePORTER application 10150529, Modulation of innate immune cellular homeostasis and inflammation resolution (5R01HL115835-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10150529. Licensed CC0.

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