The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation

• Published in: American journal of respiratory and critical care medicine Vol. 210; no. 4; pp. 497 - 507
• Main Authors: Crouser, Elliott D, Julian, Mark W, Locke, Landon W, Bicer, Sabahattin, Mitchell, Jonah R, Singha, Arindam, Kramer, Patrick J, Rajaram, Murugesan V S, Raman, Subha V
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15-08-2024
• Subjects: Aldosterone - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Captopril - pharmacology; Captopril - therapeutic use; Cytochrome P-450 CYP11B2; Cytokines - metabolism; Endocrine system; Eplerenone - pharmacology; Eplerenone - therapeutic use; Female; Granuloma - drug therapy; Hormones; Humans; Inflammation; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Losartan - pharmacology; Losartan - therapeutic use; Male; Medical treatment; Middle Aged; Mineralocorticoid Receptor Antagonists - pharmacology; Mineralocorticoid Receptor Antagonists - therapeutic use; Pathophysiology; Peptidyl-Dipeptidase A - metabolism; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Sarcoidosis; Sarcoidosis - drug therapy; Sarcoidosis - physiopathology; Spironolactone - pharmacology; Spironolactone - therapeutic use; ACE1; angiotensin receptor 1; mineralocorticoid receptor; CYP11B2; granuloma
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202402-0265OC

Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation.
We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses.
Using an established
model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis.
Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1β, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone.
The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.