Swirski, Filip, PhD
Research
Monocyte heterogeneity
Existence of monocyte subsets in circulation raises the possibility that monocytes are committed for specific function prior to tissue infiltration. Monocytes and their progeny have long been understood as "plastic" cells, capable of adapting to their local environment. Commitment in the circulation is a departure from this paradigm and may reconcile the perhaps contradictory activities attributed to these cells. It is conceivable that the eventual phenotype monocytes acquire in tissue depends on a sequence of ontogenically (cell dictates environment) and environmentally (environment dictates cell) integrated cues and checkpoints. The emerging picture then, positions monocyte subsets and their progeny as active participants in a vast immune regulatory network, rather than as downstream responders of ongoing inflammation. By extension, the circulatory system is a reservoir of functionally distinct components and may be an attractive target for discriminate therapeutic intervention. The primary interest of my lab is to chart the migratory and functional profile of monocytes and their progeny in health and disease. Experiments utilize state-of-the-art animal models, classical cell biology tools, molecular profiling, and recently developed in vivo molecular imaging and therapeutic technologies that interrogate monocyte biology at multiple resolutions, from the whole animal to a single cell. The projects interact closely with local imaging, immunology and cardiovascular groups and with outside collaborators. Currently, we have focused our interests on the role of monocyte subsets in atherosclerosis.
In atherosclerosis
Atherosclerosis is a complex chronic disease and a leading cause of myocardial infarction and stroke. At present, the dominant conceptual approaches to therapy involve manipulation of lipid metabolism and manipulation of inflammatory processes. Targeting inflammatory processes is an attractive option; since the late 1970s, inflammation has shaped our understanding of the disease and several agents that target leukocyte recruitment and retention are currently in preclinical trials.
Monocytes and macrophages are widely regarded as key cellular protagonists of atherosclerosis; not only do they promote disease through release of inflammatory mediators, but also, as lipid-rich foam cells, they become part of the disease's physical bulk. Their inhibition or ablation may seem, at first, as a clear and simple therapeutic objective. Nevertheless, monocytes are integral to the health of the organism; they are motile circulating leukocytes that patrol the vasculature, replenish tissue with macrophages, and respond to injury, infection and various "danger signals". Their indiscriminate targeting would interfere with normal homeostasis and immunity, and is therefore therapeutically nonviable. The discovery that monocytes are comprised of distinct subsets in human, mouse, and other mammals suggests specialization of function, and has stimulated interest in approaches that discriminate between "harmful" and "beneficial" subsets. Our studies test the hypothesis that monocyte subsets participate differentially in atherosclerosis. We aim to identify how differential accumulation of monocyte subsets influences the lesional environment, to modulate monocyte subsets therapeutically and evaluate impact on disease progression, and to profile monocyte subsets in human atherosclerosis.