Hmgb1-TLR4-IL-23-IL-17A axis promote ischemia-reperfusion injury in a cardiac transplantation model

H Zhu, J Li, S Wang, K Liu, L Wang, L Huang - Transplantation, 2013 - journals.lww.com
H Zhu, J Li, S Wang, K Liu, L Wang, L Huang
Transplantation, 2013journals.lww.com
Background Cardiac transplantation is the last resort for patients with end-stage heart
failure. Ischemia-reperfusion (IR) injury is a major issue in cardiac transplantation.
Inflammatory processes play a major role in myocardial IR injury. However, the cellular and
molecular immune mechanisms of myocardial IR injury remain elusive. Methods Hearts of
C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 hr and then
transplanted into syngeneic recipient. The involvement of high-mobility group box 1 …
Background
Cardiac transplantation is the last resort for patients with end-stage heart failure. Ischemia-reperfusion (IR) injury is a major issue in cardiac transplantation. Inflammatory processes play a major role in myocardial IR injury. However, the cellular and molecular immune mechanisms of myocardial IR injury remain elusive.
Methods
Hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 hr and then transplanted into syngeneic recipient. The involvement of high-mobility group box 1 (Hmgb1) and interleukin (IL)-17A was assessed in functional assays by neutralizing Hmgb1 or IL-17A.
Results
IL-17A was elevated after myocardial IR injury in cardiac transplantation. IL-17A was predominantly produced by γδT cells rather than CD4+ or CD8+ T cells infiltrated into the cardiac isografts. Neutralizing antibody against IL-17A or γδTCR attenuated cardiomyocyte apoptosis and neutrophil recruitment. Furthermore, a neutralizing IL-23p19 antibody decreased the level of IL-17A and neutrophil infiltration. Importantly, IL-23 and IL-17A were reduced after inhibition of macrophages and could not be induced in TLR4-/-mice after IR injury. Meanwhile, Hmgb1 increased after IR injury and the Hmgb1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and ameliorated myocardial IR injury.
Conclusion
The Hmgb1-TLR4-IL-23-IL-17A axis contributes to cardiomyocyte apoptosis, neutrophil accumulation and IR injury in cardiac transplantation.
Lippincott Williams & Wilkins