Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis
Satoshi Nakamizo, Yuki Sugiura, Yoshihiro Ishida, Yoko Ueki, Satoru Yonekura, Hideaki Tanizaki, Hiroshi Date, Akihiko Yoshizawa, Teruasa Murata, Kenji Minatoya, Mikako Katagiri, Seitaro Nomura, Issei Komuro, Seishi Ogawa, Saeko Nakajima, Naotomo Kambe, Gyohei Egawa, Kenji Kabashima
Satoshi Nakamizo, Yuki Sugiura, Yoshihiro Ishida, Yoko Ueki, Satoru Yonekura, Hideaki Tanizaki, Hiroshi Date, Akihiko Yoshizawa, Teruasa Murata, Kenji Minatoya, Mikako Katagiri, Seitaro Nomura, Issei Komuro, Seishi Ogawa, Saeko Nakajima, Naotomo Kambe, Gyohei Egawa, Kenji Kabashima
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Research Article Dermatology Immunology

Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis

Abstract

Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2–positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.

Authors

Satoshi Nakamizo, Yuki Sugiura, Yoshihiro Ishida, Yoko Ueki, Satoru Yonekura, Hideaki Tanizaki, Hiroshi Date, Akihiko Yoshizawa, Teruasa Murata, Kenji Minatoya, Mikako Katagiri, Seitaro Nomura, Issei Komuro, Seishi Ogawa, Saeko Nakajima, Naotomo Kambe, Gyohei Egawa, Kenji Kabashima

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Figure 5

FBP1-positive macrophages switch to PPP as the dominant route for glucose metabolism.

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FBP1-positive macrophages switch to PPP as the dominant route for glucos...
(A) Schematic diagram of glucose metabolized by the glycolytic system or via the PPP. (B) Heatmap showing metabolomic changes for each macrophage subset in all skin scRNA-Seq data (5 healthy subjects and 3 patients). Mono, monocytes. (C) Representative immunofluorescence staining in healthy (n = 3) and sarcoidosis samples (lung, n = 3; heart, n = 1; lymph node, n = 3) for expression of G6PD in gray, FBP1 in red, CD163 in green, and DAPI in blue. Scale bars: 100 μm. (D) H&E-stained sections and imaging for MS analysis of NADPH in the skin of sarcoidosis patients. Dotted lines indicate giant cells Scale bars: 500 μm (left); 100 μm (right).