Aberrant Lipid Metabolism in Macrophages Is Associated with Granuloma Formation in Sarcoidosis.

Abstract

<b>Rationale:</b> Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. <b>Objectives:</b> To understand whether macrophages from patients with nonresolving chronic sarcoidosis are predisposed to macrophage aggregation and granuloma formation and whether modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. <b>Methods:</b> Macrophages were cultivated <i>in vitro</i> from isolated peripheral blood CD14⁺ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses and phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from patients with sarcoidosis and a myeloid <i>Tsc2</i>-specific sarcoidosis mouse model were analyzed for validatory experiments. <b>Measurements and Main Results:</b> Monocyte-derived macrophages from patients with chronic sarcoidosis spontaneously formed extensive granulomas <i>in vitro</i> compared with healthy control participants. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. <i>In vitro</i> patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both <i>in vitro</i> and <i>in vivo</i> in a sarcoidosis mouse model. <b>Conclusions:</b> Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.