TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction.
TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction.
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TLR3导致小鼠心肌梗死后持续自噬和心力衰竭
DOI：
10.1111/jcmm.13328
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发表时间：
2018-01
影响因子：
5.3
通讯作者：
Lin L
中科院分区：
文献类型：
--
作者：
Gao T;Zhang SP;Wang JF;Liu L;Wang Y;Cao ZY;Hu QK;Yuan WJ;Lin L
Toll样受体（TLR）是参与宿主防御入侵微生物的重要免疫受体。最近的研究表明，某些TLR激活免疫自噬以消除微生物。目前还不清楚TLR是否调节自噬在心脏中发挥作用。本研究探讨了这一问题。在培养的心肌细胞中观察到TLR 3的激活增加了自噬组分的蛋白水平，包括LC 3-II，一种自噬诱导的特异性标志物，和p62/SQSTM 1，一种自噬受体，通常在自噬的最后一步降解。用串联mRFP-GFP-LC 3腺病毒转染和使用自噬通量抑制剂氯喹的结果都表明，心肌细胞中的TLR 3促进自噬诱导而不影响自噬通量。基因敲除实验表明TRIF依赖性途径介导TLR 3的自噬作用。在慢性心肌梗死小鼠模型中，观察到持续性自噬，伴随着TLR 3表达上调和TLR 3-Trif信号传导增加。TLR 3的种系敲除（KO）抑制自噬，减少梗死面积，减轻心力衰竭并改善存活率。这些保护作用通过体内施用自噬诱导剂雷帕霉素来消除。与在培养的心肌细胞中获得的结果类似，TLR 3-KO不能阻止小鼠心脏中的自噬通量。此外，这项研究未能检测到炎症参与TLR 3-KO衍生的保护，因为野生型和TLR 3-KO心脏的炎症活性相当。结论是上调的TLR 3表达和信号传导有助于MI后持续的自噬，这促进心力衰竭和致死性。
Toll‐like receptors (TLRs) are essential immunoreceptors involved in host defence against invading microbes. Recent studies indicate that certain TLRs activate immunological autophagy to eliminate microbes. It remains unknown whether TLRs regulate autophagy to play a role in the heart. This study examined this question. The activation of TLR3 in cultured cardiomyocytes was observed to increase protein levels of autophagic components, including LC3‐II, a specific marker for autophagy induction, and p62/SQSTM1, an autophagy receptor normally degraded in the final step of autophagy. The results of transfection with a tandem mRFP‐GFP‐LC3 adenovirus and use of an autophagic flux inhibitor chloroquine both suggested that TLR3 in cardiomyocytes promotes autophagy induction without affecting autophagic flux. Gene‐knockdown experiments showed that the TRIF‐dependent pathway mediated the autophagic effect of TLR3. In the mouse model of chronic myocardial infarction, persistent autophagy was observed, concomitant with up‐regulated TLR3 expression and increased TLR3‐Trif signalling. Germline knockout (KO) of TLR3 inhibited autophagy, reduced infarct size, attenuated heart failure and improved survival. These protective effects were abolished by in vivo administration of an autophagy inducer rapamycin. Similar to the results obtained in cultured cardiomyocytes, TLR3‐KO did not prevent autophagic flux in mouse heart. Additionally, this study failed to detect the involvement of inflammation in TLR3‐KO‐derived protection, as wild‐type and TLR3‐KO hearts were comparable in inflammatory activity. It is concluded that up‐regulated TLR3 expression and signalling contributes to persistent autophagy following MI, which promotes heart failure and lethality.
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DOI：
10.1152/ajpheart.00398.2006
发表时间：
2007-01-01
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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影响因子：
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作者：
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DOI：
10.1016/j.bbadis.2013.10.006
发表时间：
2014-01
影响因子：
6.2
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