2. Academic Validation
  3. Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2

Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2

  • Int Immunopharmacol. 2023 Jun 9;121:110401. doi: 10.1016/j.intimp.2023.110401.
Lijia Yuan 1,  Yong Wang 2,  Youlian Chen 3,  Xiaoyin Chen 4,  Shun Li 2,  Xueyan Liu 5
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medicine College of Jinan University, Shenzhen 518020, China; Department of Traditional Chinese Medicine, Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, 601 Huangpu Road, Guangzhou 510632, China.
  • 2 Majory Biotechnology Company Limited, Shenzhen 518110, China.
  • 3 Department of Critical Care Medicine, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medicine College of Jinan University, Shenzhen 518020, China.
  • 4 Department of Traditional Chinese Medicine, Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, 601 Huangpu Road, Guangzhou 510632, China. Electronic address: tchenxiaoyin@jnu.edu.cn.
  • 5 Department of Critical Care Medicine, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medicine College of Jinan University, Shenzhen 518020, China. Electronic address: liuxueyandr@163.com.
PMID: 37302371 DOI: 10.1016/j.intimp.2023.110401
Abstract

Sepsis, a life-threatening condition whereby immune dysregulation develops, is one of the major causes of death worldwide. To date, there is still no clinically effective therapeutic method for sepsis. As a natural product from traditional Chinese medicine, Shikonin has been demonstrated to have pleiotropic medical effects, including anti-tumor, anti-inflammation, and relieving sepsis. PD-L1, as the receptor of PD-1, was also involved in exacerbating sepsis by inducing immunosuppression, but the relationship between them is still unclear. In this study, we aimed to evaluate the effect of Shikonin on modulating PD-L1 expression and its contact with PKM2. The results showed that Shikonin significantly decreased the levels of sepsis mice serum inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ), interleukin-1β (IL-1β) and maintain the percentage of T cells from the spleen and significantly reduce the Apoptosis of splenocytes in LPS-induced sepsis mice. Our data also demonstrated that Shikonin significantly decreased PD-L1 expression on macrophages, not PD-1 expression on T cells in vivo and in vitro. Additionally, we revealed that Shikonin attenuated PD-L1 expression on macrophages and was associated with downregulating phosphorylation and nuclear import of PKM2, which could bind to the HRE-1 and HRE-4 sites of the PD-L1 promoter. As the present research was conducted in sepsis mice model and macrophage cell line, further study is required to evaluate Shikonin to regulate PD-L1 by targeting PKM2 in clinical samples.

Keywords

Macrophage; PD-L1; PKM2; Sepsis; Shikonin.

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