*Purpose: 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. In recent years, mesenchymal stem cell (MSC) emerges as a promising cell-based therapy. The reparative effects of MSC largely dependent on its unique immunosuppressive property, which is primed and regulated by the microenvironments.

*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 function. 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 not only in the acute phase of IRI, but also during the recovery stage, and the HMGB1 upregulation is correlated with the injury severity. We found that HMGB1 could diminish the immunosuppressive capacity of MSC in the presence of pro-inflammatory cytokines in vitro and in vivo. Toll like receptor 4 (TLR4)-mediated inducible nitric oxide synthase (iNOS) inhibition might contribute to the effect of HMGB1 on MSCs. Importantly, we further demonstrated that HMGB1 blocking strategies would augment the therapeutic efficacy of MSCs on renal IRI.

*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.

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