# The role of Trem2-expressing macrophages in atherosclerosis

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $16,806

## Abstract

PROJECT SUMMARY
Macrophages are the central inflammatory cell types in atherosclerotic lipid-laden plaques. However, the
influence of macrophage phenotype on the development of plaques remains unclear. Work from our lab has
recently described a subset of tissue macrophages that appears in contexts associated with extracellular lipid
accumulation. These macrophages were termed Lipid-Associated Macrophages (LAMs) on the basis of their
gene expression profile by single cell profiling and localization around extracellular lipids. LAMs are characterized
by the expression of the single transmembrane protein Trem2, both as a marker and as an essential driver of
LAM generation. Our findings suggest that Trem2 drives the expression of genes involved in lipid metabolism.
In addition, Trem2 has been found to act as a sensor for lipids and lipoproteins. Thus, Trem2 may function as a
pattern-recognition receptor for signals of extracellular lipid accumulation, which in turn drives a conserved
immune response aimed to reduce the burden of extracellular lipid in a disease such as atherosclerosis.
However, the role of Trem2-expressing macrophages in atherosclerosis remains unknown. In addition, the
molecular mechanisms that induce Trem2 expression are unknown. Thus, the central hypothesis of this proposal
is that Trem2 drives a tissue-specialized expression profile of macrophages that can be induced in response to
a signal of extracellular lipid accumulation, and the function of this macrophage subset is to reduce the
pathological accumulation of lipid in atherosclerosis. To test this hypothesis, two specific aims are proposed:
Aim 1 is to determine the role of Trem2 in atherosclerosis by comparing atherosclerotic burden and immune cell
phenotypes in atherosclerotic plaques of mice genetically lacking Trem2 and their littermate controls using both
the Ldlr-/- and Apoe-/- model of atherosclerosis. In Aim 2, inducers of Trem2 expression will be identified using a
novel Trem2 reporter mouse, combined with in vitro macrophage cultures and treatment conditions. I have
already generated the toolbox needed to address my specific aims, including genetic models and preliminary
data. Taken together, the completion of these studies will fundamentally advance our knowledge of a newly
discovered immune response in the context of tissue metabolic dysregulation, and pioneer actionable targets
whereby tissue physiology can be modulated by immunotherapy in disease. In addition, this work aligns with my
training goals by allowing me to use cutting-edge experimental, computational, and conceptual tools at the
forefront of an interdisciplinary field linking immunology and metabolism, to initiate my career in academia.

## Key facts

- **NIH application ID:** 10464928
- **Project number:** 1F31HL160065-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Patrick Robert Lundgren
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $16,806
- **Award type:** 1
- **Project period:** 2022-04-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464928

## Citation

> US National Institutes of Health, RePORTER application 10464928, The role of Trem2-expressing macrophages in atherosclerosis (1F31HL160065-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464928. Licensed CC0.

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