Toll-like receptor 4-mediated endoplasmic reticulum stress induces intestinal paneth cell damage in mice following CLP-induced sepsis.
Toll-like receptor 4-mediated endoplasmic reticulum stress induces intestinal paneth cell damage in mice following CLP-induced sepsis.
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Toll样受体4介导的内质网应激诱导CLP诱导的脓毒症小鼠肠道潘氏细胞损伤。
DOI：
10.1038/s41598-022-19614-6
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发表时间：
2022-09-10
影响因子：
4.6
通讯作者：
Mu, Lingjie
中科院分区：
文献类型：
--
作者：
Wang, Yijie;Zhang, Dapeng;Li, Congxin;Wu, Xue;He, Chen;Zhu, Xiaolin;Zhao, Haiyan;Mu, Lingjie
TLR4在脓毒症小鼠各脏器中均明显升高。TLR4在脓毒症肠上皮细胞损伤中的作用机制尚不清楚。采用组织学、聚合酶链反应、western-blot等方法评价TLR4在CLP小鼠肠道Paneth细胞损伤中的作用。CLP后，TLR4的回肠表达增加了5倍以上。CLP显著增加7天死亡率，并与较高的小鼠脓毒症评分（MSS）相关，与TLR4表达升高密切相关。组织学染色显示Paneth细胞数量减少，PCR检测溶菌酶和防御素α 5（DEF-5）表达减少。值得注意的是，脓毒症组回肠中ATF6、XBP1和CHOP的表达水平升高。同时，脓毒症组未裂解的p90 ATF6明显减少，裂解的p50 ATF6明显增加。有趣的是，TAK-242改善了肠黏膜损伤，降低了ATF6、XBP1和CHOP的表达，减轻了ATF6的裂解。我们发现，增加CLP小鼠回肠中TLR4的表达水平可促进Paneth细胞的消耗，降低LYZ和DEF-5的表达。此外，我们的研究结果表明，tlr4通过激活ATF6/CHOP通路介导内质网应激的过度激活可能是脓毒症肠屏障损伤期间Paneth细胞损失和功能障碍的相关机制之一。
A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.
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影响因子：
9.3
作者：
Moser VA;Uchoa MF;Pike CJ
通讯作者：
Pike CJ
影响因子：
64.8
作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
通讯作者：
Gregorieff, Alex
影响因子：
3.4
作者：
Liu, Liyan;Guo, Yuecheng;Wang, Xingpeng
通讯作者：
Wang, Xingpeng
DOI：
10.1007/978-1-0716-1488-4_1
发表时间：
2021-01-01
期刊：
SEPSIS
影响因子：
--
作者：
Drechsler, Susanne;Osuchowski, Marcin
通讯作者：
Osuchowski, Marcin
吗啡通过以TLR依赖性方式损害肠道屏障功能来诱导小鼠细菌易位。
影响因子：
3.7
作者：
Meng J;Yu H;Ma J;Wang J;Banerjee S;Charboneau R;Barke RA;Roy S
通讯作者：
Roy S