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SLC15A3 plays a crucial role in pulmonary fibrosis by regulating macrophage oxidative stress

Cell Death & Differentiation volume 31, pages 417–430 (2024)Cite this article

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal and irreversible disease with few effective treatments. Alveolar macrophages (AMs) are involved in the development of IPF from the initial stages due to direct exposure to air and respond to external oxidative damage (a major inducement of pulmonary fibrosis). Oxidative stress in AMs plays an indispensable role in promoting fibrosis development. The oligopeptide histidine transporter SLC15A3, mainly expressed on the lysosomal membrane of macrophages and highly expressed in the lung, has proved to be involved in innate immune and antiviral signaling pathways. In this study, we demonstrated that during bleomycin (BLM)- or radiation-induced pulmonary fibrosis, the recruitment of macrophages induced an increase of SLC15A3 in the lung, and the deficiency of SLC15A3 protected mice from pulmonary fibrosis and maintained the homeostasis of the pulmonary microenvironment. Mechanistically, deficiency of SLC15A3 resisted oxidative stress in macrophages, and SLC15A3 interacted with the scaffold protein p62 to regulate its expression and phosphorylation activation, thereby regulating p62-nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant stress pathway protein, which is related to the production of reactive oxygen species (ROS). Overall, our data provided a novel mechanism for targeting SLC15A3 to regulate oxidative stress in macrophages, supporting the therapeutic potential of inhibiting or silencing SLC15A3 for the precautions and treatment of pulmonary fibrosis.

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Fig. 1: SLC15A3 expression was significantly increased in pulmonary fibrosis.
Fig. 2: SLC15A3 deficiency protects mice from BLM-induced pulmonary fibrosis.
Fig. 3: Deficiency of SLC15A3 alters immune microenvironment of lung.
Fig. 4: SLC15A3 influences the progression of pulmonary fibrosis by regulating oxidative stress response.
Fig. 5: SLC15A3 regulates oxidative stress response of macrophages through p62-NRF2 pathway.
Fig. 6: Overexpression of SLC15A3 reduces the expression of p62.
Fig. 7: Interaction of SLC15A3 and p62.
Fig. 8: A proposed schematic diagram for the role of SLC15A3 in pulmonary fibrosis by modulating the redox microenvironment in macrophages.

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The data analyzed during this study are included in this article and the supplemental data files.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82073927), the Zhejiang Province Natural Science Foundation of China (LY23H310004) and the Zhejiang Provincial Medicine and Health Science Foundation (grant No. 2024KY191). We thank Prof. Huifang Tang (School of Basic Medical Sciences, Zhejiang University) for helping us develop the BALF collecting system; Kui Zeng and Haihong Hu (College of Pharmaceutical Sciences, Zhejiang University) for the guidance of animal experiments and management of instruments; Dan Wu (Research and Service Center, College of Pharmaceutical Sciences, Zhejiang University) for her technical support of confocal laser scanning microscopy; Cheng Ma (Core Facilities, Zhejiang University School of Medicine) for his technical support.

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  1. These authors contributed equally: Jun Luo, Ping Li.

  2. These authors jointly supervised this work: Huidi Jiang, Yuqing Wang.

Authors and Affiliations

  1. Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

    Jun Luo, Ping Li, Minlei Dong, Yingqiong Zhang, Shuanghui Lu, Mingyang Chen, Hui Zhou & Huidi Jiang

  2. Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People’s Hospital, Hangzhou, China

    Ping Li & Nengming Lin

  3. Jinhua Institute of Zhejiang University, Jinhua, China

    Huidi Jiang

  4. Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People’s Hospital, Hangzhou, China

    Yuqing Wang

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Contributions

JL, PL, HJ, and YW designed research; JL, PL, MD, and YW performed research; YZ, MC, SL, HZ, NL, and YW contributed reagents/analytic tools; JL, MD, YZ, MC, and SL analyzed data; and JL, PL, HJ, and YW wrote the paper.

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Correspondence to Huidi Jiang or Yuqing Wang.

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Luo, J., Li, P., Dong, M. et al. SLC15A3 plays a crucial role in pulmonary fibrosis by regulating macrophage oxidative stress. Cell Death Differ 31, 417–430 (2024). https://doi.org/10.1038/s41418-024-01266-w

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