Non-Classical Action of the Mineralocorticoid Receptor in Macrophages: At the Crossroads of Inflammation and Cardiovascular Disease.

Abstract

The Mineralocorticoid Receptor (MR) is a multifunctional nuclear steroid receptor which is responsible the actions of two classes of physiologic ligands: mineralocorticoids (aldosterone) and glucocorticoids (corticosterone in rodents). Mineralocorticoid receptor antagonists provide pleiotropic beneficial effects which culminate in a marked reduction in mortality of patients with cardiovascular disease. Since, inflammation is a common thread which connects the beneficial actions of MR antagonists, we tested the hypothesis that they act as direct immunomodulatory agents.

To test this hypothesis we generated a macrophage specific MR knockout mouse (MMRKO) to identify MR dependant macrophage actions, and illustrate the importance macrophage MR in cardiovascular inflammation. Through broad transcriptional analysis we show that glucocorticoid occupied MR is necessary for efficient classical macrophage activation and represses alternative macrophage activation programs. In vitro, macrophage MRKO synergizes with PPAR-gamma and the glucocorticoid receptor to enhance alternative activation. While ablation of glucocorticoid occupied MR mimics the actions of MR antagonists, it did not overlap with the effect of aldosterone, suggesting glucocorticoid and aldosterone occupied MR have markedly different activities.

In vivo, MMRKO mimics MR antagonists and protects against cardiac hypertrophy, fibrosis and vascular damage. This is despite a salt dependant day-time increase in systolic pressure, heart rate, and pulse pressure. Cardiac injury results in the recruitment of classically activated macrophages and a repression in alternative activation markers both of which were mitigated in MMRKO mice. Together these data implicate some macrophage actions as protective role in the inflammatory response to cardiac stress.

These studies demonstrate that macrophage glucocorticoid•MR is an important control point in macrophage polarization in innate immunity and likely illustrates a conserved ancestral function of MR. We conclude that glucocorticoid•MR control of macrophage polarization is a critical target for the beneficial cardiovascular action of MR antagonists.