Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination.
Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination.
复制标题
DAMP 诱导的自噬通过促进 TRAF6 泛素化促进缺血再灌注损伤肺部的炎症反应。
DOI：
10.1038/cdd.2017.1
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发表时间：
2017-04
影响因子：
12.4
通讯作者：
Zhan Z
中科院分区：
文献类型：
--
作者：
Liu X;Cao H;Li J;Wang B;Zhang P;Dong Zhang X;Liu Z;Yuan H;Zhan Z
肺缺血再灌注损伤是各种心肺手术后最常见的并发症之一。由释放的损伤相关分子模式（DAMP）触发的炎症反应加剧了肺组织损伤。然而，关于自噬在肺I/R损伤的发病机制中的作用知之甚少。在这里，我们报告了各种炎症相关和自噬相关基因的快速上调，这有助于在小型猪肺I/R损伤模型中的炎症反应。左肺I/R损伤触发炎性细胞因子的产生并激活自噬通量，如在粗肺组织和肺泡巨噬细胞中所证明的。这与DAMP的释放有关，如高迁移率族蛋白B1（HMGB 1）和热休克蛋白60（HSP 60）。事实上，用重组HMGB 1或HSP 60处理诱导肺泡巨噬细胞中的自噬，而通过敲低ATG 7或BECN 1的自噬抑制显著减少肺泡巨噬细胞中DAMP触发的炎性细胞因子（包括IL-1β、TNF和IL 12）的产生。这似乎是由于MAPK和NF-κB信号转导的活化减少。此外，在DAMP处理的肺泡巨噬细胞中，ATG 7或BECN 1的敲低抑制了Lys 63（K63）连接的TNF受体相关因子6（TRAF 6）的泛素化。一致地，用3-MA处理抑制I/R损伤的肺组织中TRAF 6的K63连接的泛素化。总的来说，这些结果表明，在肺I/R损伤期间由DAMP触发的自噬通过增强TRAF 6的K63连接的泛素化以及下游MAPK和NF-κB信号传导的激活来放大炎症反应。
Lung ischemia-reperfusion (I/R) injury remains one of the most common complications after various cardiopulmonary surgeries. The inflammation response triggered by the released damage-associated molecular patterns (DAMPs) aggravates lung tissue damage. However, little is known about the role of autophagy in the pathogenesis of lung I/R injury. Here, we report that a variety of inflammation-related and autophagy-associated genes are rapidly upregulated, which facilitate the inflammation response in a minipig lung I/R injury model. Left lung I/R injury triggered inflammatory cytokine production and activated the autophagy flux as evidenced in crude lung tissues and alveolar macrophages. This was associated with the release of DAMPs, such as high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60). Indeed, treatment with recombinant HMGB1 or HSP60 induced autophagy in alveolar macrophages, whereas autophagy inhibition by knockdown of ATG7 or BECN1 markedly reduced DAMP-triggered production of inflammatory cytokines including IL-1β, TNF and IL12 in alveolar macrophages. This appeared to be because of decreased activation of MAPK and NF-κB signaling. Furthermore, knockdown of ATG7 or BECN1 inhibited Lys63 (K63)-linked ubiquitination of TNF receptor-associated factor 6 (TRAF6) in DAMP-treated alveolar macrophages. Consistently, treatment with 3-MA inhibited K63-linked ubiquitination of TRAF6 in I/R-injured lung tissues in vivo. Collectively, these results indicate that autophagy triggered by DAMPs during lung I/R injury amplifies the inflammatory response through enhancing K63-linked ubiquitination of TRAF6 and activation of the downstream MAPK and NF-κB signaling.