Project 1 ABSTRACT Studies over the last decade have identified the presence of 3 subsets of blood monocytes. The three subsets are: classical or `inflammatory' monocytes, nonclassical or `patrolling' monocytes, and intermediate monocytes. Elevated numbers of classical monocytes are correlated with progression of human cardiovascular disease (CVD), but less is known about the functions of intermediate and nonclassical monocytes in human CVD. Many published clinical studies have lumped the nonclassical and intermediate human monocytes together, making it impossible to discern their unique functions. Thus, valid functions of these subsets in humans remain elusive. What is clear is that monocytes play key roles in human CVD and that individually targeting different monocyte subsets may modulate the immune-cell dysregulation that occurs in atherosclerosis. Triggering Receptor Expressed On Myeloid Cells-Like 4 (TREML4) is a receptor that is preferentially expressed on myeloid cells. TREML4 recognizes dying and necrotic cells, provides protective immunity, and is required for TLR7 signaling. We found that murine nonclassical monocytes have very high expression of TREML4. Interestingly, a single nucleotide polymorphism (SNP) in TREML4 has been linked with coronary artery calcium (CAC) in two human cohorts. Thus, we propose to study the impact of TREML4 on atherosclerosis progression. We hypothesize that TREML4 is anti-inflammatory and is increased in human and mouse monocytes during atherosclerosis progression to protect against inflammation. The goals of Project 1 are: 1) to test whether TREML4 is atheroprotective, 2) to identify functions of TREML4 on monocyte subsets in atherosclerosis, 3) to test whether TREML4+ monocytes in humans are functionally associated with cardiovascular disease, and 4) to identify how human monocytes are phenotypically and functionally changed in CVD. We will test our hypotheses in the following aims:
Specific Aim 1 will test whether TREML4 is atheroprotective.
Specific Aim 2 will test how a single nucleotide polymorphism (rs2803496) in human TREML4 known to be linked to CAC functionally changes human monocyte subsets, and how TREML4 is linked to CVD in humans. We will study subjects in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who have CAC scores =0 (low risk CVD) or >300 (high risk CVD). At the conclusion of our studies, we will know the function of TREML4 in atherosclerosis and if TREML4 is a new biomarker for CAC levels and CVD risk. We will know how human monocytes change during cardiovascular disease, if there are ethnic-specific or gender-specific monocyte changes, and we will have identified new targets for regulating human monocyte subset function in CVD.

Public Health Relevance

Project 1 NARRATIVE Circulating monocytes represent 4% and 10% of mice and human blood leukocytes respectively. Emerging evidence suggests that monocytes can initiate inflammatory responses, survey and clean up the vasculature, recognize pathogens, and help kill tumor cells. Some monocytes are precursors to macrophages in tissue, where they function to aid in tissue homeostasis. However, monocytes and macrophages phenotypically change during atherosclerosis development, and in some cases, can exacerbate disease. As cardiovascular disease remains a leading cause of death in the US, understanding how these cells phenotypically change during atherosclerosis is critically important. The focus of this project is to study how human monocyte subsets functionally change in atherosclerosis. To do this we will use innovative mass cytometry methods in monocytes from a large cohort of human subjects with elevated coronary artery calcium levels, which are directly correlated to cardiovascular risk.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Chen, Jue
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Jolla Institute
La Jolla
United States
Zip Code
Prohaska, Thomas A; Que, Xuchu; Diehl, Cody J et al. (2018) Massively Parallel Sequencing of Peritoneal and Splenic B Cell Repertoires Highlights Unique Properties of B-1 Cell Antibodies. J Immunol 200:1702-1717
Kobiyama, Kouji; Vassallo, Melanie; Mitzi, Jessica et al. (2018) A clinically applicable adjuvant for an atherosclerosis vaccine in mice. Eur J Immunol 48:1580-1587
Liu, Chao; Kim, Young Sook; Kim, Jungsu et al. (2018) Modeling hypercholesterolemia and vascular lipid accumulation in LDL receptor mutant zebrafish. J Lipid Res 59:391-399
Schneider, Dina A; Choi, Soo-Ho; Agatisa-Boyle, Colin et al. (2018) AIBP protects against metabolic abnormalities and atherosclerosis. J Lipid Res 59:854-863
Kobiyama, Kouji; Ley, Klaus (2018) Atherosclerosis. Circ Res 123:1118-1120
Woller, Sarah A; Choi, Soo-Ho; An, Eun Jung et al. (2018) Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States. Cell Rep 23:2667-2677
Tsimikas, Sotirios (2018) In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. J Lipid Res 59:741-744
Choi, Soo-Ho; Wallace, Aaron M; Schneider, Dina A et al. (2018) AIBP augments cholesterol efflux from alveolar macrophages to surfactant and reduces acute lung inflammation. JCI Insight 3:
Tsimikas, Sotirios; Fazio, Sergio; Ferdinand, Keith C et al. (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol 71:177-192
Liu, Chao; Han, Tianxu; Stachura, David L et al. (2018) Lipoprotein lipase regulates hematopoietic stem progenitor cell maintenance through DHA supply. Nat Commun 9:1310

Showing the most recent 10 out of 16 publications