Mineralocorticoid receptors in immune cells: Emerging role in cardiovascular disease
Introduction
The mineralocorticoid receptor (MR) is a member of the steroid receptor family of hormone activated transcription factors. The classical MR ligand is the adrenal hormone aldosterone that regulates blood pressure by activating MR in the kidney to promote renal sodium retention. Ample clinical data support that aldosterone and MR contribute to the risk and poor clinical outcomes for patients with hypertension, heart failure, myocardial infarction (MI), and stroke [1], [2], [3]. Indeed, MR antagonist drugs improve outcomes in cardiovascular patients disproportionate to modest changes in blood pressure and renal sodium handling, supporting extra-renal mechanisms [4], [5], [6], [7]. Over the past two decades, it has become clear that the MR is expressed and functional in tissues outside the kidney [8], [9], [10], [11] and that these extra-renal MRs contribute to cardiovascular disease. The role of vascular MRs in cardiovascular disease has been previously reviewed [12], [13], [14]. A role for inflammation in the initiation and progression of cardiovascular diseases has emerged. A critical contribution of chronic inflammation to atherosclerosis progression and complications (MI and stroke) has been known for some time and, more recently, inflammation has also been implicated in hypertension and heart failure. Although MR activation contributes to cardiovascular inflammation, the direct contribution of MR in immune cells to cardiovascular disease has only recently been considered and the available data in support of this new concept is summarized in this review. We specifically focus here on the role of MR in macrophages, dendritic cells (DCs), T lymphocytes and B lymphocytes. As there is limited data on the role of MR in other immune cells in cardiovascular disease, including neutrophils and monocytes, these cells are not considered here.
The Renin–Angiotensin–Aldosterone System (RAAS) is a hormonal cascade that regulates electrolyte balance and blood pressure [15]. In response to decreased blood pressure, the kidney releases the protease renin to cleave circulating angiotensinogen, culminating in the production of angiotensin II (AngII) by angiotensin converting enzyme (ACE). AngII acts through two angiotensin receptors (AT1R and AT2R) and specifically via the AT1R on adrenal cells to promote aldosterone release. Aldosterone activates renal MRs to enhance renal re-absorption of sodium and water, thereby increasing blood pressure [16]. The classical MR ligand is aldosterone (or deoxycorticosterone (DOCA) in rodents), however, the receptor also binds glucocorticoids, including cortisol, with equal affinity. Since cortisol circulates at substantially higher concentrations than aldosterone, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is thought to be necessary for aldosterone responsiveness in epithelial cells by locally inactivating cortisol [17]. With the discovery of MR in non-epithelial cells, the determination of the endogenous ligand in these cells has been controversial. In steroid free media in vitro or with high dose infusion in vivo, aldosterone will activate MR in all cells in which it is expressed. Some non-epithelial cells, including vascular smooth muscle and endothelial cells, appear to express 11β-HSD2 and hence are thought to be aldosterone-responsive [9], [10], while cardiomyocytes do not and hence cortisol may be the cardiac MR ligand [18]. Thus, we also review what is known about expression of 11β-HSD2 in leukocytes. Whether there are other mechanisms protecting MR from being occupied by cortisol, thereby conferring aldosterone-responsiveness to MR in leukocytes that do not express 11β-HSD2, remains to be explored.
RAAS inhibitors, including ACE inhibitors, angiotensin receptor blockers, and MR antagonists, are used extensively in the treatment of hypertension and heart failure and to reduce the incidence of MI, stroke, and death [4], [5], [6], [19], [20]. Components of the RAAS have recently been identified in immune cells, raising the possibility that inhibition of RAAS in immune cells could be contributing to the beneficial effects of these drugs in cardiovascular patients. Here we review recent advances in our understanding of the role of MR in immune cells including macrophages, about which there is substantial new information, followed by dendritic cells, T lymphocytes and B lymphocytes, about which less is known. In the first section, we summarize available data on expression of RAAS components in each type of leukocyte and the impact of MR activation on the immunologic functions of each immune cell. In the second section, we review what is known about the roles of MR in each immune cell in cardiovascular disease.
Section snippets
RAAS expression in macrophages
Macrophages are innate immune cells that arise from circulating monocytes upon infiltration into tissues. Bone marrow derived macrophages express both the MR and the related glucocorticoid receptor (GR). Levels of the two steroid receptors in macrophages are modulated in a stimulus specific way, with lipopolysaccharide (LPS) up-regulating GR expression and down-regulating MR expression, and interferon gamma (IFN-γ) increasing both MR and GR expression [21]. Table 1 summarizes what is known to
Leukocyte MR in hypertension
The new appreciation for the existence of functional MR in leukocytes supports the potential for leukocyte MR to contribute directly to cardiovascular disease, perhaps by promoting the pro-inflammatory M1 macrophage phenotype or by enhancing Th1/Th17 T lymphocyte polarization (Fig. 2). MR contributes substantially to the development of hypertension by promoting volume retention in the kidney and likely also by increasing tone in the vasculature [36], [37]. Hyperaldosteronism is thought to
Summary and future directions
All together, the literature supports an active role for the immune system in the development, progression, and outcome of cardiovascular disease. Exploration of the specific roles of macrophages and of T and B lymphocyte subsets in cardiovascular function is an extremely active area of investigation. The fact that the MR is expressed in the innate and adaptive immune systems and modulates immune function opens new doors to understanding the pathogenesis of aldosterone-enhanced cardiovascular
Acknowledgments
This work was supported by grants from the National Institutes of Health (HL095590-05 (to I.Z.J.) and HL094706 (to P.A.)), from the Russo Family Charitable Foundation Trust (to I.Z.J. and P.A.) and from the Eshe Foundation (to H.H.W.).
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