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Abstract: FR-PO107

The HMGB1-IL17A Axis Promotes Neutrophil Infiltration in Renal Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wang, Jia, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital,Chengdu, Chengdu, Sichuan, China
  • Zhang, Jiong, Renal Department,Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
Background

Renal ischemia/reperfusion (I/R) injury is the leading cause of acute kidney injury (AKI), which is associated with increased morbidity and mortality. Neutrophils are first to be recruited to the site of inflammation and also play a central role in the inflammatory cascade. We reported previously that inhibition of HMGB1 release ameliorated IR-induced neutrophils infiltration in mice. However, it is poorly understood whether HMGB1 was involved in regulating and activating the IL23/IL17 axis in renal IR injury. In this study, we aim to delineate whether the HMGB1/TLR4 signaling provokes the IL23/IL-17 axis and inducing the renal IR injury in mice.

Methods

C57BL/6 mice ischemia was induced by 60 min clamping of the left renal pedicle and followed by right nephrectomy and up to 24 h of reperfusion. The involvement of HMGB1 and IL17A was assessed in functional assays by neutralizing HMGB1, IL23 or IL17A antibody, and recombinant HMGB1 (rHMGB1), IL23 or IL17A (rIL17A), respectively. Urea nitrogen, creatine kinase and lactate dehydrogenase levels were measured. Renal histopathological changes and neutrophils infiltration were assessed by immunohistochemistry. The expression of HMGB1, TLR4, IL23, IL17A were assessed by western blot analysis and mRNA expression. The levels of MCP-1, IL8 and RANTES were assessed by ELISA.

Results

IL23, IL17A and neutrophils infiltration were increased after renal IR injury in mice. HMGB1 antibody significantly ameliorated IR induced neutrophils infiltration, renal injury and IL23, IL17A levels. TLR4-/- mice following renal IR injury were treated with rHMGB1 significantly reduced the expression of IL23, IL17A and neutrophils infiltration. Furthermore, IL-23 or IL17A antibody significantly inhibited IR induced neutrophils infiltration. Moreover, HMGB1 or IL17A antibody remarkably decreased production of neutrophil chemoattractant MCP-1, IL8 and RANTES, whereas rHMGB1 or rIL17A may promote production of them.

Conclusion

These results suggested that HMGB1 facilitated the injury effect of the IL23/IL17 axis, which contributed to neutrophils infiltration in renal IR injury.

Funding

  • Government Support - Non-U.S.