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Pre-treatment twice with liposomal clodronate protects against acetaminophen hepatotoxicity through a pre-conditioning effect 被引量:2
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作者 Melissa M.Clemens Joel H.Vazquez +3 位作者 Stefanie Kennon-McGill Sandra S.McCullough Laura P.James Mitchell R.McGill 《Liver Research》 2020年第3期145-152,共8页
Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhib... Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhibitors protect against APAP injury.However,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the toxicity.To our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute pre-treatment.The aim of this study was to confirm that observation and to explore the mechanisms.Methods:We treated mice with empty liposomes(LE)or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0,2,and 6 h post-APAP.We then measured liver injury(serum alanine aminotransferase activity,histology),APAP bioactivation(total glutathione,APAP-protein adducts),oxidative stress(oxidized glutathione(GSSG)),glutamate-cysteine ligase subunit c(Gclc)mRNA,and nuclear factor erythroid 2-related factor(Nrf2)immunofluorescence.We also confirmed the ablation of macrophages by F4/80 immunohistochemistry.Results:Pre-treatment twice with LC dramatically reduced F4/80 staining,protected against liver injury,and reduced oxidative stress at 6 h post-APAP,without affecting APAP bioactivation.Importantly,Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h,indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase.Oxidative stress was lower in the LC groups at both time points.Finally,total Nrf2 immunofluorescence was higher in the LC group.Conclusions:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase.Investigators using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this possible confounder. 展开更多
关键词 Acetaminophen(APAP) Acute liver failure(ALF) Damage-associated molecular patterns(DAMPs) Drug-induced liver injury liposomal clodronate(LC) Kupffer cells Nuclear factor erythroid 2-related factor(Nrf2) Sterile inflammation Stress response
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Don’t know what you got till it’s gone:microglial depletion and neurodegeneration 被引量:1
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作者 David Graykowski Eiron Cudaback 《Neural Regeneration Research》 SCIE CAS CSCD 2021年第10期1921-1927,共7页
In the central nervous system,immunologic surveillance and response are carried out,in large part,by microglia.These resident macrophages derive from myeloid precursors in the embryonic yolk sac,migrating to the brain... In the central nervous system,immunologic surveillance and response are carried out,in large part,by microglia.These resident macrophages derive from myeloid precursors in the embryonic yolk sac,migrating to the brain and eventually populating local tissue prior to blood-brain barrier formation.Preserved for the duration of lifespan,microglia serve the host as more than just a central arm of innate immunity,also contributing significantly to the development and maintenance of neurons and neural networks,as well as neuroregeneration.The critical nature of these varied functions makes the characterization of key roles played by microglia in neurodegenerative disorders,especially Alzheimer’s disease,of paramount importance.While genetic models and rudimentary pharmacologic approaches for microglial manipulation have greatly improved our understanding of central nervous system health and disease,significant advances in the selective and near complete in vitro and in vivo depletion of microglia for neuroscience application continue to push the boundaries of research.Here we discuss the research efficacy and utility of various microglial depletion strategies,including the highly effective CSF1R inhibitor models,noteworthy insights into the relationship between microglia and neurodegeneration,and the potential for therapeutic repurposing of microglial depletion and repopulation. 展开更多
关键词 Alzheimer’s disease clodronate liposomes CSF1R depletion microglia NEURODEGENERATION neuroregeneration REPOPULATION
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