The overall goal of this project is to define the role of complement protein C1q in programming macrophage polarization in atherosclerosis. Innate immune protein C1q is often considered only for its role in the activation of the inflammatory complement cascade. However, in the absence of other complement components, C1q can also directly opsonize targets. It is a pattern recognition receptor (PRR) and is able to directly interct with phagocytic cells and activate responses. We have previously shown C1q activates macrophage phagocytosis and modulates cytokine and gene expression towards an M2-like response during apoptotic cell clearance. In the early stages of atherosclerosis, modified lipoproteins accumulate in the arterial intima leading to the formation and apoptosis of macrophage foam cells. In late stages of disease, complement activation via C1q leads to the terminal pathway of complement and deposition of the cytolytic membrane attack complex, which exacerbates pathology. However, conversely, C1q has been shown to be protective in early stages of atherosclerosis, but its precise mechanism of action has not yet been elucidated. Our central hypothesis is that complement-independent actions of C1q are polarizing macrophages towards a protective, anti-atherosclerotic phenotype during ingestion of modified lipoproteins. We have previously shown that C1q alters pathways of lipid metabolism by binding and enhancing clearance of atherogenic lipoproteins, and increases cholesterol efflux in cholesterol-loaded human macrophages. Thus, we propose to perform detailed mechanistic investigations of the pathways involved, and to identify any cross-talk between pathways of lipid metabolism and inflammatory responses. Studies will be performed in vitro, in primary isolated murine or monocyte-derived human macrophages, and macrophage cell lines and, in vivo, in mouse models of hyperlipidemia. These studies aim to identify novel pathways for the design of novel therapeutic strategies. These may include strategies to restore or augment defective apoptotic foam cell clearance, enhance or mimic anti-inflammatory macrophage polarization, and/or inhibit detrimental terminal complement pathway activation.
Atherosclerosis is the predominant contributor to cardiovascular disease, currently the leading cause of death for both men and women in the USA. This project aims to investigate the role of the innate immune system in atherosclerosis. Specifically we will be looking at how complement protein C1q modifies macrophage polarization during the removal of atherogenic lipoproteins, and identifying the molecular mechanisms involved. The ultimate goal is to identify novel therapeutic targets for treating atherosclerosis and improving public health.
|Pulanco, Marc C; Cosman, Jason; Ho, Minh-Minh et al. (2017) Complement Protein C1q Enhances Macrophage Foam Cell Survival and Efferocytosis. J Immunol 198:472-480|
|Ho, Minh-Minh; Manughian-Peter, Ayla; Spivia, Weston R et al. (2016) Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q. Atherosclerosis 253:38-46|
|Ho, Minh-Minh; Fraser, Deborah A (2016) Transcriptome data and gene ontology analysis in human macrophages ingesting modified lipoproteins in the presence or absence of complement protein C1q. Data Brief 9:362-367|