Comments
Rationale: 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.
Objectives: 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.
Methods: Macrophages were cultivated in vitro 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 Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments.
Measurements and Main Results: Monocyte-derived macrophages from patients with chronic sarcoidosis spontaneously formed extensive granulomas in vitro compared with healthy control participants. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro 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 in vitro and in vivo in a sarcoidosis mouse model.
Conclusions: 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.
* These authors contributed equally to this work.
‡ Present address: Ludwig Boltzmann Institute for Lung Health, Clinic Penzing, Vienna, Austria.
Supported by the Vienna Science and Technology Fund (WWTF) LS18-058 (to G.S. and T.W.), and the Austrian Society of Pneumology Science Grant 2022 (to C.X.L.). Furthermore, this study has been funded by the Vienna Science and Technology Fund (WWTF) through project NXT22-005 (to G.S.). Research in the T.W. laboratory was supported by the Austrian Science Fund (FWF P30857-B28, P34023-B, and P34266-B), the FWF Sonderforschungsbereich F83, and the Ann Theodore Foundation Breakthrough Sarcoidosis Initiative. G.S. was supported by a grant from the Leo Foundation (LF-OC-21-000806) and the Austrian Science Fund (FWF P31494 and PAT8019123). R.V.P. was supported by the Austrian Science Fund (P36555).
Author Contributions: C.X.L., T.W., and G.S. conceived the project. C.X.L. and A.R. designed experiments. C.X.L., A.R., and L.K. performed experiments and analyzed results. A.R. took blood and tissue biopsy samples. R.V.P. analyzed RNA-sequencing data and performed bioinformatics analyses. C.X.L., T.E.J., and N.S. performed bioinformatics analyses. C.X.L. carried out mouse experiments and analyses. A.R., M.M., K.G., C.M. and L.K. performed immunohistochemical tissue stainings. T.K. prepared single-cell–sequencing libraries. T.W., G.S., T.K., C.B., M.H., A.C., and Y.P. provided supervision, support and expertise. C.X.L. wrote the manuscript. A.R., T.W., G.S., L.K., and R.V.P. added to and modified the manuscript draft. All authors read and approved the final manuscript.
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Originally Published in Press as DOI: 10.1164/rccm.202307-1273OC on February 14, 2024
Author disclosures are available with the text of this article at www.atsjournals.org.
