Sarcoidosis is a disease of unknown cause that forms granulomas in various organs, has no specific treatment established. Here, we investigated the mechanism of granuloma formation by applying single-cell RNA sequencing to skin biopsy specimens from human patients with sarcoidosis. In cutaneous sarcoidosis granuloma lesions, there was an increase in macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, which are known to be elevated in the serum of sarcoidosis patients. These macrophages were hypermetabolic, especially in the pentose phosphate pathway (PPP). Immunostaining of organs from patients with sarcoidosis revealed elevated expression of PPP-related enzymes in granuloma lesions beyond the skin, including those in the lung, lymph nodes, and heart. When human peripheral blood monocytes were cultured with interferon gamma and CD40L, along with concanavalin A (a C-type lectin), there was an elevation in PPP-related enzymes in macrophages, and granulomas with giant cells were formed. Inhibitors of the PPP pathway inhibited granuloma formation. Similarly, PPP inhibitors also suppressed granuloma formation in a mouse model. Until this study, the details and metabolic pathways of granuloma constituent cells were completely unknown. However, our findings have elucidated that macrophages with elevated PPP-related enzymes contribute to granuloma formation and that targeting PPP-related enzymes could be a therapeutic approach in granulomatous diseases.
Essential Role of the Pentose Phosphate Pathway Activation in Macrophages for Granuloma Formation in Sarcoidosis
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Poster and Podium (Block Symposium)
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Date: May 4 Presentation Time: 05:15 PM to 05:30 PM Room: Room W181