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Insufficient SIRT1 in macrophages promotes oxidative stress and inflammation during scarring

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Abstract

Macrophage is a critical regulator in wound healing and scar formation, and SIRT1 is related to macrophage activation and polarization, while the specific mechanism is still unclear. To explore the specific effects of SIRT1 in scarring, we established a skin incision mouse model and LPS-induced inflammation cell model. The expression of SIRT1 in tissue and macrophage was detected, and the level of SIRT1 was changed to observe the downstream effects. LPS-induced macrophages with or without SIRT1 deficiency were used for TMT-based quantitative proteomic analysis. SIRT1 was suppressed in scar while increased in macrophages of scar tissue. And macrophages were proven to be necessary for wound healing. In the early stage of wound healing, knockout of SIRT1 in macrophage could greatly strengthen inflammation and finally promote scarring. NADH-related activities and oxidoreductase activities were differentially expressed in TMT-based quantitative proteomic analysis. We confirmed that ROS production and NOX2 level were elevated after LPS stimulation while the Nrf2 pathway and the downstream proteins, such as Nqo-1 and HO-1, were suppressed. In contrast, the suppression of SIRT1 strengthened this trend. The NF-κB pathway was remarkably activated compared with the control group. Insufficient increase of SIRT1 in macrophage leads to over activated oxidative stress and activates NF-κB pathways, which then promotes inflammation in wound healing and scarring. Further increasing SIRT1 in macrophages could be a promising method to alleviate scarring.

Key messages

  • SIRT1 was suppressed in scar while increased in macrophages of scar tissue.

  • Inhibition of SIRT1 in macrophage leads to further activated oxidative stress.

  • SIRT1 is negatively related to oxidative stress in macrophage.

  • The elevation of SIRT1 in macrophage is insufficient during scarring.

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Data availability

Data could be acquired from the first author and corresponding authors.

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Acknowledgements

The authors would like to thank Dorsa Sinaki of Shanghai Jiaotong University School of Medicine for editing the language.

Funding

This study is supported by the National Natural Science Foundation of China (NO.81601689) and the Natural Science Foundation of Shaanxi Province (NO. 2020JM-332).

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Author notes

  1. Ting He and Xiaozhi Bai have contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Medical University, 127 Changle West Road, Xi’an, Shaanxi, 710032, China

    Ting He, Xiaozhi Bai, Yan Li, Dongliang Zhang, Zhigang Xu, Xuekang Yang, Dahai Hu & Juntao Han

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  1. Ting He
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  2. Xiaozhi Bai
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  3. Yan Li
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Contributions

Dahai Hu and Juntao Han conceived and designed the experiments. Ting He wrote the manuscript. Xiaozhi Bai and Yan Li performed the experiments. Zhigang Xu and Dongliang Zhang provide the tissue samples. Ting He and Xiaozhi Bai analyzed the data. Ting He and Juntao Han revised the paper before submission.

Corresponding authors

Correspondence to Dahai Hu or Juntao Han.

Ethics declarations

Ethics approval and consent to participate

The protocol was approved by the Ethics Committee of Xijing Hospital, affiliated with Air Force Medical University (No: XJYYLL-2018021). Hypertrophic scar (HS) and paired normal skin (NS) tissues contiguous to the scar were obtained from adult patients who suffered from hypertrophic scar and planned to receive scar resection in our department. Before surgery, all patients and their legal representatives were informed of the purpose and procedure of this study and agreed to donate excess tissue. Written informed consent was obtained from all participants or their legal representatives. The animal study was conducted in accordance with the principles of ARRIVE and approved by the Ethics Committee of Xijing Hospital (No.: XJYYLL-2018021).

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The authors declare no competing interests.

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He, T., Bai, X., Li, Y. et al. Insufficient SIRT1 in macrophages promotes oxidative stress and inflammation during scarring. J Mol Med 101, 1397–1407 (2023). https://doi.org/10.1007/s00109-023-02364-x

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  • DOI: https://doi.org/10.1007/s00109-023-02364-x

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