Cellular metabolism and macrophages regulating plaque inflammation, resolution and repair in atherosclerosis

Background:

It is a challenge to treat patients with already established atherosclerotic plaques. To do this, the chronic plaque inflammation has to be moved into a phase of resolution and repair. Macrophages are among the most prevalent cells found in plaques and have been shown to be able to adopt phenotypes that promote either inflammation or repair responses.

Aims:

We hypothesize that alternatively activated macrophages, assigned reparatory and anti-inflammatory properties, are important regulators of atherosclerotic plaque resolution and repair. Furthermore we hypothesize that reprogramming of the cellular metabolism is critical for the effector functions performed by macrophages and that targeting metabolism could be used to shift the chronic inflammation towards resolution and repair.

Work plan:

Here we will evaluate the development of atherosclerosis in mice lacking macrophage expression of Irf5 or Irf4, which are transcription factors implicated in polarization of macrophages to a proinflammatory or reparatory phenotype, and to characterize the mechanisms by which macrophages of different phenotypes contribute to atherosclerosis.

We will also evaluate plaque inflammation and resolution of atherosclerosis in mice treated with a small-molecule compound that modulates the activity of the rate-limiting glycolytic enzyme pyruvate kinase. Finally, we will continue to systematically catalogue which circulating leukocyte subsets are associated with cardiovascular risk in humans with flow cytometry in the unique prospective MDCS cohort.

Importance:

Increasing our understanding of the cellular contributors to plaque inflammation and the potential to target plaque inflammation by metabolic inhibitors could improve diagnosis, prognosis and treatment of the dangerous atherosclerotic plaque.