Free radical biology & medicine · 2025
NOD2 promotes sepsis-induced neuroinflammation by increasing brain endoplasmic reticulum stress mediated by LACC1.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yi Lingling, Chen Zhuo, Zhou Qiuping, Liu Nan, Li Qian, Wu Xinghui, Zeng Yu, Lin Yiyan, Lin Simin, Luo Lifang, Jiang Shuqi, Huang Peixian, Wang Huifang, Deng Yiyu
Аннотация
BACKGROUND: Although nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been associated with diverse inflammatory states and some neurological diseases, its role in regulating sepsis-induced neuroinflammation remains unexplored. This study aimed to determine the role of NOD2 in modulating sepsis-induced neuroinflammation and to elucidate its potential mechanisms.
METHODS: mRNA and protein expression levels of NOD2 were measured in the periventricular white matter (PWM) of C57BL/6 mice and the microglia. NOD2-/- mice were generated using the CRISPR/Cas9 technology, and the septic mouse model was established by using cecal ligation puncture (CLP). Microglia were transfected with siRNA specific to NOD2 or laccase domain-containing protein 1 (LACC1) or treated with the endoplasmic reticulum stress (ER stress) inhibitor 4-phenylbutyrate (4-PBA) in vitro under muramyl dipeptide (MDP)-induced neuroinflammation. Immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction were performed to evaluate neuroinflammation and ER stress. The ER structure was observed using transmission electron microscopy.
RESULTS: NOD2 expression level was upregulated in the mouse model of sepsis-induced neuroinflammation. The absence of NOD2 led to a protective effect against neuroinflammation, which was correlated with ER stress both in vitro and in vivo. LACC1 was identified as a notable mediator of ER stress, contributing to the exacerbation of neuroinflammation. Mechanistically, elevated NOD2 expression level promoted neuroinflammation by enhancing ER stress through LACC1. Notably, these effects were partially mitigated by LACC1 downregulation.
CONCLUSIONS: These findings highlight the pivotal role of NOD2 in promoting sepsis-induced neuroinflammation via regulating ER stress mediated by LACC1, and provide a new potential strategy for treating human neuroinflammation.
METHODS: mRNA and protein expression levels of NOD2 were measured in the periventricular white matter (PWM) of C57BL/6 mice and the microglia. NOD2-/- mice were generated using the CRISPR/Cas9 technology, and the septic mouse model was established by using cecal ligation puncture (CLP). Microglia were transfected with siRNA specific to NOD2 or laccase domain-containing protein 1 (LACC1) or treated with the endoplasmic reticulum stress (ER stress) inhibitor 4-phenylbutyrate (4-PBA) in vitro under muramyl dipeptide (MDP)-induced neuroinflammation. Immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction were performed to evaluate neuroinflammation and ER stress. The ER structure was observed using transmission electron microscopy.
RESULTS: NOD2 expression level was upregulated in the mouse model of sepsis-induced neuroinflammation. The absence of NOD2 led to a protective effect against neuroinflammation, which was correlated with ER stress both in vitro and in vivo. LACC1 was identified as a notable mediator of ER stress, contributing to the exacerbation of neuroinflammation. Mechanistically, elevated NOD2 expression level promoted neuroinflammation by enhancing ER stress through LACC1. Notably, these effects were partially mitigated by LACC1 downregulation.
CONCLUSIONS: These findings highlight the pivotal role of NOD2 in promoting sepsis-induced neuroinflammation via regulating ER stress mediated by LACC1, and provide a new potential strategy for treating human neuroinflammation.