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

Yuan, Lijia1; Wang, Yong; Chen, Youlian1; Chen, Xiaoyin3; Li, Shun2; Liu, Xueyan1

2023-08-01

10.1016/j.intimp.2023.110401

INTERNATIONAL IMMUNOPHARMACOLOGY   影响因子和分区

1567-5769

1878-1705

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 exac-erbating 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-& alpha; (TNF-& alpha;), interleukin-6 (IL-6), interferon-& gamma; (IFN-& gamma;), interleukin-1 & beta; (IL-1 & beta;) 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 macro-phages, 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.

Sepsis Shikonin PD-L1 PKM2 Macrophage

SCI

英语

第一 ; 通讯

Shenzhen Key Laboratory of Prevention and Treatment of Severe Infections[ZDSYS20200811142804014] ; Shenzhen Key Medical Discipline Construction Fund[SZXK045] ; Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ20190806155207398]

Immunology ; Pharmacology & Pharmacy

Immunology ; Pharmacology & Pharmacy

WOS:001019565400001

ELSEVIER

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Southern Univ Sci & Technol, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Crit Care Med,Affiliated Hosp 1, Shenzhen 518020, Peoples R China
2.Majory Biotechnol Co Ltd, Shenzhen 518110, Peoples R China
3.Jinan Univ, Dept Tradit Chinese Med, Integrated Chinese & Western Med Postdoctoral Res, 601 Huangpu Rd, Guangzhou 510632, Peoples R China

Yuan, Lijia,Wang, Yong,Chen, Youlian,et al. Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2[J]. INTERNATIONAL IMMUNOPHARMACOLOGY,2023,121.

Yuan, Lijia,Wang, Yong,Chen, Youlian,Chen, Xiaoyin,Li, Shun,&Liu, Xueyan.(2023).Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2.INTERNATIONAL IMMUNOPHARMACOLOGY,121.

Yuan, Lijia,et al."Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2".INTERNATIONAL IMMUNOPHARMACOLOGY 121(2023).