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Transplantation. 2013 Jun 27;95(12):1448-54. doi: 10.1097/TP.0b013e318293b7e1.

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

Author information

1
Department of Anesthesiology and The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China. hongfeizhu1973@163.com

Abstract

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.

PMID:
23677049
DOI:
10.1097/TP.0b013e318293b7e1
[Indexed for MEDLINE]

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