Introduction: Sarcoidosis is an inflammatory granulomatous disease characterized by aggregates of macrophages in one or more organs. The molecular mechanisms leading to progressive sarcoidosis remain unclear. Treatment options for such patients are also limited.

Aims/Methods: To obtain insights on the pathomechanisms underlying granuloma formation in non-resolving sarcoidosis, we included patients with progressive non-familial sarcoidosis and age-matched controls. Monocyte-derived macrophages were differentiated with GM-CSF for 6 days and assessed for spontaneous clustering. Bulk RNA-Sequencing was also performed.

Results: Macrophages from sarcoidosis patients spontaneously formed extensive granulomas in vitro compared to healthy controls. Transcriptomic analyses showed clear separation between healthy and sarcoidosis macrophages, and identified an enrichment in cholesterol metabolic processes in the upregulated genes. Macrophages differentiated in vitro and directly analyzed in skin granulomas of patients expressed important lipid scavengers and regulators and contained increased neutral lipids. Conversely, statin treatment reduced in vitro granuloma formation and lipid accumulation. Additionally, a combination of a cholesterol-deficient diet and atorvastatin treatment reduced pulmonary inflammation and granulomas in a sarcoidosis mouse model.

Conclusion: Altered cholesterol metabolism in macrophages predisposes macrophages to form granulomas in progressive sarcoidosis, and suggest cholesterol-reducing therapies as a potential treatment option. This in vitro assay that we established also provides a platform to test compounds targeting sarcoid granulomas.