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    Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

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    Author
    Zou, Lin
    He, Junyun
    Gu, Lili
    Shahror, Rami A.
    Li, Yun
    Cao, Tuoxin
    Wang, Sheng
    Zhu, Jing
    Huang, Huang
    Chen, Fengqian
    Fan, Xiaoxuan
    Wu, Junfang
    Chao, Wei
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    Date
    2021-11-19
    Journal
    Brain, Behavior, and Immunity
    Publisher
    Academic Press Inc.
    Type
    Article
    
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    See at
    https://doi.org/10.1016/j.bbi.2021.11.007
    Abstract
    Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood–brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7-/- mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3β signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation. © 2021 The Author(s)
    Sponsors
    International Anesthesia Research Society
    Keyword
    Behavior
    Cytokines
    Encephalopathy
    Extracellular RNA
    IL-6
    Innate immunity
    MicroRNA
    Neuroinflammation
    Sepsis
    TLR7
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17227
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bbi.2021.11.007
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