Normal aging hyperactivates innate immunity and reduces the medical efficacy of minocycline in brain injury

Sanuki, Rikako; Tanaka, Tomoya; Suzuki, Fumiko; Ibaraki, Kimihide; Takano, Toshiyuki

doi:10.1016/j.bbi.2019.04.023

Cited by 16 publications

(18 citation statements)

References 40 publications

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“…In flies, both closed-head and penetrating TBI leads to increased expression of AMP genes in fly heads (Katzenberger et al 2016;Ratliff et al 2016;Sanuki et al 2019).…”

Section: Mtk Expression In the Brain Is Increased By Tbi And Agingmentioning

confidence: 99%

“…Data presented here suggest that studies of individual effectors will reveal insights that are crucial for understanding how secondary injuries bring about deleterious TBI outcomes. The Drosophila TBI model is well-suited to investigate roles for individual innate immune response effectors because flies have a simpler innate immune system than mammals, but as in mammals, TBI causes rapid and prolonged activation of the innate immune response (Katzenberger et al 2013(Katzenberger et al , 2015a(Katzenberger et al , 2015b(Katzenberger et al , 2016Barekat et al 2016;Sanuki et al 2019). Flies have two major NF-B-mediated innate immune response pathways: the Toll pathway, which is homologous to mammalian TLR pathways, and the Imd pathway, which is homologous to the mammalian TNF receptor pathway (Lemaitre and Hoffmann 2007;Bergman et al 2017).…”

Section: Loss Of a Single Effector Of The Innate Immune Response Altementioning

confidence: 99%

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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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“…In flies, both closed-head and penetrating TBI leads to increased expression of AMP genes in fly heads (Katzenberger et al 2016;Ratliff et al 2016;Sanuki et al 2019).…”

Section: Mtk Expression In the Brain Is Increased By Tbi And Agingmentioning

confidence: 99%

Section: Loss Of a Single Effector Of The Innate Immune Response Altementioning

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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show abstract

“…We and others have developed fly TBI models to investigate the pathways that control development of secondary injuries following TBI (Katzenberger et al 2013(Katzenberger et al , 2015a(Katzenberger et al , 2015bBarekat et al 2016;Sen et al 2017;Lee et al 2019;Putnam et al 2019;Sanuki et al 2019;Shah et al 2019;Saikumar et al 2020). Our model uses a spring-based instrument called a High-impact trauma (HIT) device to inflict physical trauma by rapid acceleration-deceleration forces (Katzenberger et al 2013(Katzenberger et al , 2015a(Katzenberger et al , 2015b(Katzenberger et al , 2015c(Katzenberger et al , 2016Fischer et al 2018;Swanson et al 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Flies that have sustained a TBI share behavioral and physiologic characteristics with mammals, including temporary incapacitation, ataxia, transient hyperglycemia, intestinal barrier dysfunction, progressive neurodegeneration, and reduced lifespan. Additionally, like mammals, the innate immune response in flies is rapidly and persistently activated following TBI (Katzenberger et al 2013(Katzenberger et al , 2015a(Katzenberger et al , 2015bBarekat et al 2016;Sanuki et al 2019). Expression of AMP genes substantially increases within 30 min after TBI and is sustained for more than 24 h (Katzenberger et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish

et al. 2020

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Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by NF-κB transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-κB factors Dif and Relish (Rel), respectively. Here, we found by mass spectrometry that Rel protein level increased in fly heads at 4-8 h after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel, by CRISPR/Cas9 editing. When heterozygous but not homozygous, the Reldel mutation reduced mortality at 24 h after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygosity for Reldelon mortality was modulated by genetic background and diet. To identify genes that facilitate effects of Reldel on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel, and Reldel/Reldel flies at 4 h following TBI. Only a few genes changed expression more than two-fold in +/Reldel flies relative to +/+ and Reldel/Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.

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“…These proinflammatory cytokines can be transmitted through the impaired bloodbrain barrier (BBB) to overactivate microglia, resulting in hippocampal neuroinflammation in POCD [23]. The neural system of aged individuals is more susceptible than that of young adults [24,25]. Our previous study showed that a single surgery (splenectomy) did not impair the spatial reference memory of young adult mice in spite of the increased IL-1β/IL-6 and activated microglia [26].…”

Section: Discussionmentioning

confidence: 99%

Multiple Anesthesia/Surgery Cannot Impair Reference Memory in Adult Mice

Zhou

et al. 2020

Mediators of Inflammation

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Postoperative cognitive dysfunction increases mortality and morbidity in perioperative patients. Numerous studies have demonstrated that multiple surgery/anesthesia during the neurodevelopmental period affects cognitive function, whereas a single anesthesia/surgery rarely causes cognitive dysfunction in adults. However, whether adults who undergo multiple anesthesia/surgery over a short period will experience cognitive dysfunction remains unclear. In this study, central nervous system inflammation and changes in cholinergic markers were investigated in adult mice subjected to multiple laparotomy procedures over a short period of time. The results showed that despite the increased expression of IL-6 and TNF-α in the hippocampus after multiple operations and the activation of microglia, multiple anesthesia/surgery did not cause a decline in cognitive function in adult mice. There were no changes in the cholinergic markers after multiple anesthesia/surgery.

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Normal aging hyperactivates innate immunity and reduces the medical efficacy of minocycline in brain injury

Cited by 16 publications

References 40 publications

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

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

Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish

Multiple Anesthesia/Surgery Cannot Impair Reference Memory in Adult Mice

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