Role of Toll-like receptor mediated signaling in traumatic brain injury

Shi, Hang; Hua, Xiaodong; Kong, Delian; Stein, Donald G.; Fang, Hua

doi:10.1016/j.neuropharm.2018.07.022

Cited by 61 publications

(35 citation statements)

References 128 publications

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“…As our results verified, the inhibition of the inflammatory response could be if not all, part of the reason, while other remaining potential factors also need to be assessed in the future. The results of our in vitro experiments indicated that miR-146a could be used not only for treating SAH also for some other hemorrhage or ischemia-associated diseases in central nervous system, such as cerebral hemorrhage, traumatic brain injury, or ischemic stroke, because TLR pathways are widely activated in the pathological process (Wang et al, 2013;Shi et al, 2019); however, miR-146a related studies in these areas are limited.…”

Section: Discussionmentioning

confidence: 97%

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

et al. 2020

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Microglial activation and sustained inflammation in the brain can lead to neuronal damage. Hence, limiting microglial activation and brain inflammation is a good therapeutic strategy for inflammatory-associated central nervous disease. MiR-146a is a promising therapeutic microRNA, since it can negatively regulate the inflammatory response. We thus investigated the expression changes of miR-146a after experimental induction of a subarachnoid hemorrhage (SAH) in vivo and in vitro, and we assessed the anti-inflammatory effects of miR-146a in microglial cells in vitro. Primary microglial cells were preincubated with miR-146a before hemoglobin (Hb) treatment. The results indicated that miR-146a decreased gene expression of Hb-induced pro-inflammatory cytokines (TNF-α and IL-1β) and phenotype-related genes (iNOS and CD86) through IRAK1/TRAF6/NF-κB or MAPK signaling pathways, suggesting its pro-resolution activity in microglia. However, contrary to the LPS-induced microglia or macrophage activation model, we did not observe an elevation in miR-146a after activation. Overall, our findings demonstrated that miR-146a was involved in the regulation of brain inflammation and could be considered a novel therapeutic agent for treating brain inflammation.

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Section: Discussionmentioning

confidence: 97%

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

et al. 2020

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“…Activation of NF-κB-mediated innate immune response pathways, including Toll-like receptor (TLR) pathways, is one of the earliest and most robust secondary responses to primary injuries in TBI patients and mammalian TBI models ( Kumar and Loane 2012 ; Needham et al 2019 ). Of the six TLRs in mammals that are expressed on the surface of cells, only TLR2 and TLR4 have been examined in TBI, and mutation of one or both receptors was found to attenuate detrimental outcomes of TBI ( Zu and Zha 2012 ; Laird et al 2014 ; Jiang et al 2018 ; Shi et al 2019 ). Most TBI studies have focused on TLR4, which is expressed on the surface of immune cells and stimulates production of multiple effectors, including the proinflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and IL-6 as well as factors implicated in inflammatory diseases such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) ( Zhu et al 2014 ; Jiang et al 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of the Antimicrobial Peptide Metchnikowin Protects Against Traumatic Brain Injury Outcomes in Drosophila melanogaster

Swanson

Rimkus

Ganetzky

et al. 2020

G3 Genes|Genomes|Genetics

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Neuroinflammation is a major pathophysiological feature of traumatic brain injury (TBI). Early and persistent activation of innate immune response signaling pathways by primary injuries is associated with secondary cellular injuries that cause TBI outcomes to change over time. We used a Drosophila melanogaster model to investigate the role of antimicrobial peptides (AMPs) in acute and chronic outcomes of closed-head TBI. AMPs are effectors of pathogen and stress defense mechanisms mediated by the evolutionarily conserved Toll and Immune-deficiency (Imd) innate immune response pathways that activate Nuclear Factor kappa B (NF-kB) transcription factors. Here, we analyzed the effect of null mutations in 10 of the 14 known Drosophila AMP genes on TBI outcomes. We found that mutation of Metchnikowin (Mtk) was unique in protecting flies from mortality within the 24 h following TBI under two diet conditions that produce different levels of mortality. In addition, Mtk mutants had reduced behavioral deficits at 24 h following TBI and increased lifespan either in the absence or presence of TBI. Using a transcriptional reporter of gene expression, we found that TBI increased Mtk expression in the brain. Quantitative analysis of mRNA in whole flies revealed that expression of other AMPs in the Toll and Imd pathways as well as NF-kB transcription factors were not altered in Mtk mutants. Overall, these results demonstrate that Mtk plays an infection-independent role in the fly nervous system, and TBI-induced expression of Mtk in the brain activates acute and chronic secondary injury pathways that are also activated during normal aging.

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“…Various TLRs are also expressed in neurons, astrocytes, and in microglial cells, and they are conducive to the immunological responses of the CNS [32–34]. Emerging evidence suggests that TLRs play fundamental roles in brain development and homeostasis [28, 35, 36]. TLR7 is widely expressed in immune cells, intestinal cells, lung cells, and neural cells, wherein it is also able to detect and respond to specific viral RNAs, single-stranded oligoribonucleotides, siRNAs, and microRNAs, leading to intracellular signaling pathway activation and cytokine production [10, 11, 19, 37].…”

Section: Discussionmentioning

confidence: 99%

EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

Luo

Wang

et al. 2019

PLoS Pathog

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As a neurotropic virus, human Enterovirus 71 (EV71) infection causes hand-foot-and-mouth disease (HFMD) and may develop severe neurological disorders in infants. Toll-like receptor 7 (TLR7) acts as an innate immune receptor and is also a death receptor in the central nervous system (CNS). However, the mechanisms underlying the regulation of TLR7-mediated brain pathogenesis upon EV71 infection remain largely elusive. Here we reveal a novel mechanism by which EV71 infects astrocytes in the brain and induces neural pathogenesis via TLR7 and interleukin-6 (IL-6) in C57BL/6 mice and in human astroglioma U251 cells. Upon EV71 infection, wild-type (WT) mice displayed more significant body weight loss, higher clinical scores, and lower survival rates as compared with TLR7-/- mice. In the cerebral cortex of EV71-infected mice, neurofilament integrity was disrupted, and inflammatory cell infiltration and neurodegeneration were induced in WT mice, whereas these were largely absent in TLR7-/- mice. Similarly, IL-6 production, Caspase-3 cleavage, and cell apoptosis were significantly higher in EV71-infected WT mice as compared with TLR7-/- mice. Moreover, EV71 preferentially infected and induced IL-6 in astrocytes of mice brain. In U251 cells, EV71-induced IL-6 production and cell apoptosis were suppressed by shRNA-mediated knockdown of TLR7 (shTLR7). Moreover, in the cerebral cortex of EV71-infected mice, the blockade of IL-6 with anti-IL-6 antibody (IL-6-Ab) restored the body weight loss, attenuated clinical scores, improved survival rates, reduced the disruption of neurofilament integrity, decreased cell apoptotic induction, and lowered levels of Caspase-3 cleavage. Similarly, in EV71-infected U251 cells, IL-6-Ab blocked EV71-induced IL-6 production and cell apoptosis in response to viral infection. Collectively, it’s exhibited TLR7 upregulation, IL-6 induction and astrocytic cell apoptosis in EV71-infected human brain. Taken together, we propose that EV71 infects astrocytes of the cerebral cortex in mice and human and triggers TLR7 signaling and IL-6 release, subsequently inducing neural pathogenesis in the brain.

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Role of Toll-like receptor mediated signaling in traumatic brain injury

Cited by 61 publications

References 128 publications

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

Loss of the Antimicrobial Peptide Metchnikowin Protects Against Traumatic Brain Injury Outcomes in Drosophila melanogaster

EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production

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