Hmgb1-TLR4-IL-23-IL-17A Axis Promote Ischemia-Reperfusion Injury in a Cardiac Transplantation Model
Hmgb1-TLR4-IL-23-IL-17A Axis Promote Ischemia-Reperfusion Injury in a Cardiac Transplantation Model
复制标题
DOI：
10.1097/tp.0b013e318293b7e1
复制
发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Hongfei Zhu;Jun Li;Sihua Wang;Kebin Liu;Li Wang;Lili Huang
中科院分区：
文献类型：
--
作者：
Hongfei Zhu;Jun Li;Sihua Wang;Kebin Liu;Li Wang;Lili Huang
背景心脏移植是终末期心力衰竭患者的最后手段。缺血再灌注(IR)损伤是心脏移植的主要问题。炎症过程在心肌IR损伤中起重要作用。然而，心肌缺血再灌注损伤的细胞和分子免疫机制仍不清楚。方法将C57BL/6小鼠心脏灌流，在布雷施奈德冷冻液中保存8h后移植到同基因受体。通过中和高迁移率族蛋白1(HMGB1)和白介素17A(IL-17A)，在功能检测中评估HMGB1和IL-17A的参与。结果心脏移植心肌IR损伤后IL-17A升高。IL-17A主要由T细胞产生，而不是由CD4+或CD8+T细胞渗入同种异体心脏。抗IL-17A或TCR的中和抗体可减少心肌细胞的凋亡和中性粒细胞的募集。此外，中和性IL-23p19抗体可降低IL-17A水平和中性粒细胞的浸润。重要的是，IL-23和IL-17A在巨噬细胞被抑制后降低，在TLR4-/-小鼠IR损伤后不能被诱导。同时，IR损伤后HMGB1升高，HMGB1抑制剂甘草酸显著减少IL-23和IL-17A的产生，减轻心肌IR损伤。结论HMGB1-TLR4-IL-23-IL-17A轴参与了心脏移植后心肌细胞的凋亡、中性粒细胞聚集和IR损伤。
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 T cells rather than CD4+ or CD8+ T cells infiltrated into the cardiac isografts. Neutralizing antibody against IL-17A or TCR 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.