Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone

Abstract

The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models.

Figure 1

Corticoid signal transduction. Circulating corticoids diffuse across the cell membrane. While mineralocorticoids (MC) almost exclusively bind to the mineralocorticoid receptor (MR), glucocorticoids (GC) can bind either to MR or to the glucocorticoid receptor (GR). GC binding to its receptors is modulated by 11-β hydroxysteroid dehydrogenase type 2 (11β-HSD2), by converting GCs to its inactive form, cortisone. Upon ligand binding, these nuclear receptors uncouple from their complex with Heat Shock Proteins (HSPs), dimerize, and translocate to the nucleus. Depending on the bound ligands nature, GR and MR can either homodimerize or heterodimerize. These dimers then bind to Hormonal Response Elements (HREs) on promoter regions and different genes will be transcribed.

Figure 2

Immunological effect of MR antagonism and knockout. In vitro treatment with pharmacological antagonist of MR has suggested that this receptor could be important to keep immune function, because its antagonism directly modulates the proinflammatory cytokines and chemokines production and cell migration. These results also have been reported in other cell types such as adipocytes, which today are known as a source of inflammatory mediators. In animal models the treatment with MR antagonist or KO animals to myeloid MR has supported the notion of MR as immune regulator.

Figure 3

Aldosterone as proinflammatory stimulus. Available data links aldosterone excess with inflammatory phenotype. Clinical studies performed in patients with primary aldosteronism have demonstrated that aldosterone induces inflammatory and oxidative changes, whereas MR antagonism or controlling aldosterone levels contributes to return at homeostatic conditions. Similarly, in vitro experiments demonstrate that myeloid immune cells respond to aldosterone, inducing the expression and secretion of proinflammatory cytokines. This modulation of innate immune cells directly impacts the polarization of adaptive immune response toward Th17 phenotype.