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 6

Treatment of in vitro giant cell model by inhibition of the PPP.

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Treatment of in vitro giant cell model by inhibition of the PPP. (A) Fol...
(A) Fold induction of FBP1 and G6PD mRNA in Con A, IFN-γ, and anti-CD40 antibodies stimulated (stim) monocytes, as analyzed by quantitative PCR (n = 3). (B) Measurement of intracellular NADP and NADPH levels in the in vitro giant cell model (n = 4). (C) Schematic diagram of metabolic pathways and inhibitors of glucose and NADPH metabolized by the glycolytic system or by the PPP. (D and E) Giemsa staining (D) and bar graphs (E) of monocytes stimulated with Con A, IFN-γ, and anti-CD40 antibodies, with or without DMSO, DPI, FBPi, and 6AN (n = 4). (F and G) Giemsa staining (F) and giant cell count (G) of 3 day cultures stimulated with Con A, IFN-γ, and anti-CD40 antibodies followed by incubation with DMSO, FBPi, or 6AN for 3 days (n = 3–5). (H and I) Giemsa staining (H) and bar graphs (I) of monocytes stimulated with Con A, IFN-γ, and anti-CD40 antibodies, with or without DMSO, 6AN, or G6PDi (n = 5). Data are representative of at least 3 independent experiments. Scale bars: 100 μm. (A and B) *P < 0.05, unpaired t test. (E, G, and I) *P < 0.05, Dunnett’s multiple-comparisons test.