Control of atherogenic inflammation through lipidome remodeling

Cardiovascular disease is the main cause of mortality in the world. The dominant cause of this disease is atherosclerosis, a blood vessel disorder that is driven by accumulation of fatty deposits inside arteries. We now know that not only dietary fats and cholesterol drive atherosclerosis, but also patients' own immune cells, such as macrophages. These cells are specialized scavengers and thus are drawn to fatty deposits in arteries. At deposit sites macrophages try to contain fats and lipids, often dying as a result and releasing danger signals that attract additional immune cells. Build-up of fats and recruited cells form a plaque in the vessel that over time blocks blood flow. And while plaque formation may make the patient feel sick, it is the next step in disease development that is most deadly. Inflammation in the plaque generates tissue-destroying enzymes that can rupture the plaque inducing blood clots that can block blood flow to the heart or brain. This vessel blockage causes deadly strokes and heart attacks. Therefore, stopping or slowing down inflammation initiated by macrophages in response to ingestion of fat could reduce the most deadly effects of atherosclerosis. In the past year we have focused on analysis of a novel link that we have identified, between a gene that controls the composition of intracellular lipids and an anti-inflammatory transcription factor whose activity is controlled by these lipids. The biggest advance that we made was identification of a lysophosphatidylcholine, a constitutive part of proatherogenic low density lipoproteins, as a molecule that controls induction of our lipid regulator. This enabled us to analyze global changes in macrophage gene expression as well as carry out a whole genome CRISPR knockout screen to identify a set of genes that control responses to lysophosphatidylcholines. We use this data to build a system wide picture of changes in macrophages gene expression in response to molecules that drive atherogenesis. This will greatly simplify our search for key regulators that can be targeted to prevent pro-atherogenic inflammatory changes in human immune cells.

Atherosclerosis is the underlying pathology of major cardiovascular diseases that are among the leading causes of death and disability in Norway. A key initiating event in development of atherosclerosis is ingestion by macrophages of lipids deposited on the arterial wall. As these macrophages accumulate significant loads of lipids they turn into foam cells that form the core of future atherosclerotic plaques and drive inflammatory processes detrimental to the patient. Our overall aim is to reduce the impact of atherogenic inflammation and to slow down the development of atherosclerosis. To achieve this aim we focus on the scavenger receptor-like molecule Apoptosis Inhibitor in Macrophages (AIM). AIM is a multifunctional protein that promotes uptake of modified lipids, such as oxidized LDL, and sustain survival of macrophages, facilitating their transformation into foam cells. We have now discovered that AIM also regulates the inflammatory state of macrophages and controls production of atherosclerotic plaque destabilizing enzymes. Our data suggests AIM remodels macrophage lipid content and as a result changes the activity of the RORalpha transcriptional factor. Our project will identify and characterize the regulators, mediators and targets of this novel signaling pathway. As a result, we expect to have a deeper understanding of the interaction between metabolic and inflammatory signaling that promotes human atherogenesis. We will identify and test novel targets that could allow us to control atherogenic signaling events, improving our chances to reduce progression of atherosclerosis. Also, we will attempt to reduce detrimental atherogenic inflammation by targeting the AIM controlled immunometabolic pathway in patient-derived atheromas. This will establish the translational value of our approach and provide a basis for development of new treatments.