High-mobility group box 1 protein antagonizes the immunosuppressive capacity and therapeutic effect of mesenchymal stem cells in acute kidney injury

Journal of Translational Medicine

Benkang Shi¹  Xigao Liu¹  Yan Li¹  Shuo Wang²  Ming Xu²  Weitao Zhang²  Chao Zhang²  Tongyu Zhu²  Yigang Zeng²  Cheng Yang²  Ruiming Rong²  Tianshu Yang³  Anil Chandraker⁴  Songjie Cai⁴ 

[1] Department of Urology, Qilu Hospital of Shandong University;Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation;Shanghai Tenth People’s Hospital, Tongji University School of Medicine;Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School;

关键词: Mesenchymal stem cell;    HMGB1;    Ischemia–reperfusion injury;    Acute kidney injury;    Cell therapy;   

DOI  :  10.1186/s12967-020-02334-8

来源: DOAJ

【 摘 要 】

Abstract Background Kidney ischemia reperfusion injury (IRI) is a common cause of acute kidney injury and an unavoidable consequence of kidney transplantation and still lacks specific therapeutics. Recently, mesenchymal stem cell (MSC) has been emerging as a promising cell-based therapy for IRI in the context of transplantation. MSC negatively regulates the secretion of pro-inflammatory as well as the activation of immune cells during IRI through its unique immunosuppressive property. Methods We employed mice kidney IRI model and MSC cell line to monitor the IRI related checkpoints. siRNAs were utilized to knock down the potential key factors for mechanistic analysis. Statistical analysis was performed by using one-way ANOVA with Tukey’s post hoc procedure by SPSS. Results The expression of high-mobility group box 1 protein (HMGB1) is increased in the acute phase as well as the recovery stage of IRI. Importantly, the HMGB1 upregulation is correlated with the injury severity. HMGB1 diminishes the MSC induced immunosuppressive capacity in the presence of pro-inflammatory cytokines in vitro. Toll like receptor 4 (TLR4)-mediated inducible nitric oxide synthase (iNOS) inhibition contributes to the negative effect of HMGB1 on MSCs. HMGB1-TLR4 signaling inhibition augments the therapeutic efficacy of MSCs in mice renal IRI model. Conclusions These findings demonstrate that HMGB1 plays a crucial role in shaping the immunoregulatory property of MSCs within the microenvironments, providing novel insights into the crosstalk between MSCs and microenvironment components, suggesting HMGB1 signals as a promising target to improve MSC-based therapy.

【 授权许可】

Unknown