Notch-Hes-1 axis controls TLR7-mediated autophagic death of macrophage via induction of P62 in mice with lupus.
Notch-Hes-1 axis controls TLR7-mediated autophagic death of macrophage via induction of P62 in mice with lupus.
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Notch-Hes-1 轴通过诱导狼疮小鼠中的 P62 来控制 TLR7 介导的巨噬细胞自噬死亡。
DOI：
10.1038/cddis.2016.244
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发表时间：
2016-08-18
影响因子：
9
通讯作者：
Hou Y
中科院分区：
文献类型：
--
作者：
Li X;Liu F;Zhang X;Shi G;Ren J;Ji J;Ding L;Fan H;Dou H;Hou Y
巨噬细胞死亡增加被认为是系统性红斑狼疮（SLE）的致病因素，自噬功能障碍可能导致细胞不适当死亡。但自噬在SLE发病过程中对巨噬细胞的影响尚不清楚。在这里，我们发现MRL/lpr狼疮易感小鼠中巨噬细胞的死亡率和自噬水平显著增加。Toll样受体7（TLR 7）的激活在体外以自噬依赖但非半胱天冬酶依赖的方式触发巨噬细胞死亡。此外，P62/SQSTM 1被认为在选择性自噬中起重要作用。我们还证明了P62/SQSTM 1是TLR 7诱导的自噬所必需的，并且P62的敲低抑制了R848诱导的细胞死亡和LC 3 II蛋白的积累。Notch信号作为细胞间通讯的重要介质，参与细胞命运的决定。我们的研究结果表明，TLR 7的激活也上调了Notch 1的表达，特别是其下游靶基因Hairy和分裂增强子1（Hes-1）在巨噬细胞中的表达。值得注意的是，我们发现Hes-1作为一种转录因子，通过调节P62的表达来控制TLR 7诱导的自噬。此外，为了在体内确认上述结果，制备了TLR 7激动剂咪喹莫特（IMQ）诱导的狼疮小鼠模型。IMQ处理小鼠的脾巨噬细胞表现出增加的自噬和细胞死亡以及Notch 1和Hes-1的表达增强。我们的结果表明，Notch 1-Hes-1信号传导通过调节狼疮小鼠中的P62来控制TLR 7诱导的巨噬细胞自噬死亡。
The increased death of macrophages has been considered as a pathogenic factor for systemic lupus erythematosus (SLE), and dysfunction of autophagy may contribute to improper cell death. However, the effect of autophagy on macrophage during the pathogenesis of SLE is still unclear. Here we found that the death rate and autophagy level of macrophages significantly increased in MRL/lpr lupus-prone mice. Activation of toll-like receptor 7 (TLR7) triggered macrophage death in an autophagy-dependent but caspase-independent way in vitro. Moreover, P62/SQSTM1 is thought to have an essential role in selective autophagy. We also demonstrated that P62/SQSTM1 was required for TLR7-induced autophagy, and knockdown of P62 suppressed R848-induced cell death and LC3II protein accumulation. As an important mediator for cell–cell communication, Notch signaling is responsible for cell-fate decisions. Our results showed that activation of TLR7 also upregulated the expression of Notch1, especially its downstream target gene Hairy and enhancer of split 1 (Hes-1) in macrophages. Of note, we found that Hes-1, as a transcriptional factor, controlled TLR7-induced autophagy by regulating P62 expression. Furthermore, to confirm the above results in vivo, TLR7 agonist imiquimod (IMQ)-induced lupus mouse model was prepared. Splenic macrophages from IMQ-treated mice exhibited increased autophagy and cell death as well as enhanced expressions of Notch1 and Hes-1. Our results indicate that Notch1-Hes-1 signaling controls TLR7-induced autophagic death of macrophage via regulation of P62 in mice with lupus.
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影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
13.3
作者：
Burbano, C.;Vasquez, G.;Rojas, M.
通讯作者：
Rojas, M.
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
5.4
作者：
Monsalve, Eva;Ruiz-Garcia, Almudena;Diaz-Guerra, Maria Jose M.
通讯作者：
Diaz-Guerra, Maria Jose M.
DOI：
10.1073/pnas.1014156108
发表时间：
2011-01-25
影响因子：
11.1
作者：
Fujita, Ken-ichi;Maeda, Daisuke;Srinivasula, Srinivasa M.
通讯作者：
Srinivasula, Srinivasa M.