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Theranostics 2024; 14(7):2794-2815. doi:10.7150/thno.94482 This issue Cite

Research Paper

Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice

Yaling Chen^1†, Tong Wang^1†, Fuxiang Liang^2†, Jia Han², Zhiling Lou², Yifan Yu², Jinsheng Li², Tianwei Zhan³, Yuqing Gu⁴, Lingjun Dong⁵, Bo Jiang^4,6, Weiping Zhang^1✉, Ming Wu^2✉, Yunbi Lu^1✉

1. Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, China.
2. Department of Thoracic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
3. Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang Province, China.
4. Department of Pharmacology, School of Pharmacy, Zhejiang University, Hangzhou, Zhejiang Province, China.
5. Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang Province, China.
6. Department of Clinical Pharmacology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
† These authors contributed equally to this work; they were assigned as co-first authors, and the authorship order is assigned according to the time they enrolled as graduate students.

✉ Corresponding authors: Weiping Zhang, Ming Wu or Yunbi Lu; Department of Pharmacology, School of Basic Medical Sciences, and Department of Thoracic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; weiping601edu.cn; iwuming22edu.cn; yunbiedu.cn. More

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated.

Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice. In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis.

Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages (Nampt^fl/fl;Cx3cr1^CreER) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in Nampt^fl/fl;Cx3cr1^CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway.

Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.

Keywords: pulmonary fibrosis, nicotinamide phosphoribosyltransferase, macrophage, M2 polarization, STAT6

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