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Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells.

ABSTRACT: Our laboratories forged the concept of macrophage delivery of protein antioxidants to attenuate neuroinflammation and nigrostriatal neurodegeneration in Parkinson's disease. Notably, the delivery of the redox enzyme, catalase, incorporated into a polyion complex micelle ('nanozyme') by bone marrow-derived macrophages protected nigrostriatum against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication. Nonetheless, how macrophage delivery of nanozyme increases the efficacy of catalase remains unknown.In this study, we examined the transfer of nanozyme from macrophages to brain microvessel endothelial cells, neurons and astrocytes.Facilitated transport of the nanozyme from macrophages to endothelial, neuronal and glial target cells occurred through endocytosis-independent mechanisms that involved fusion of cellular membranes, macrophage bridging conduits and nanozyme lipid coatings. Nanozyme transfer was operative across an artificial blood-brain barrier and showed efficient reactive oxygen species decomposition.This is the first demonstration, to our knowledge, that drug-loaded macrophages discharge particles to contiguous target cells for therapeutic brain enzyme delivery. The data shown are of potential value for the treatment of neurodegenerative disorders and notably, Parkinson's disease.

SUBMITTER: Haney MJ

PROVIDER: S-EPMC3166447 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells.

Haney Matthew J MJ Zhao Yuling Y Li Shu S Higginbotham Sheila M SM Booth Stephanie L SL Han Huai-Yun HY Vetro Joseph A JA Mosley R Lee RL Kabanov Alexander V AV Gendelman Howard E HE Batrakova Elena V EV

Nanomedicine (London, England) 20110331 7

<h4>Background</h4>Our laboratories forged the concept of macrophage delivery of protein antioxidants to attenuate neuroinflammation and nigrostriatal neurodegeneration in Parkinson's disease. Notably, the delivery of the redox enzyme, catalase, incorporated into a polyion complex micelle ('nanozyme') by bone marrow-derived macrophages protected nigrostriatum against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication. Nonetheless, how macrophage delivery of nanozyme increases the efficacy ...[more]

PMID: 21449849

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Project description:BACKGROUND:Lymphotoxin (LT) is a lymphokine mainly expressed in lymphocytes. LT? binds one or two membrane-associated LT? to form LT?2?1 or LT?1?2 heterotrimers. The predominant LT?1?2 binds to LT? receptor (LT?R) primarily expressed in epithelial and stromal cells. Most studies on LT?R signaling have focused on the organization, development, and maintenance of lymphoid tissues. However, the roles of LT?R signaling in the nervous system, particularly in neurogenesis, remain unknown. Here, we investigated the role of LT?R-mediated NF?B signaling in regulating neural lineage differentiation. METHODS:The C57BL/6J wild-type and GFAP-dnI?B? transgenic mice were used. Serum-free embryoid bodies were cultured from mouse embryonic stem cells and further induced into neural stem/progenitor cells (NSCs/NPCs). Primary neurospheres were cultured from embryonic and adult mouse brains followed by monolayer culture for amplification/passage. NF?B activation was determined by adenovirus-mediated NF?B-firefly-luciferase reporter assay and p65/RelB/p52 nuclear translocation assay. LT?R mRNA expression was evaluated by quantitative RT-PCR and LT?R protein expression was determined by immunohistochemistry and Western blot analysis. Multilabeled immunocytochemistry or immunohistochemistry followed by fluorescent confocal microscopy and quantitative analysis of neural lineage differentiation were performed. Graphing and statistical analysis were performed with GraphPad Prism software. RESULTS:In cultured NSCs/NPCs, LT?1?2 stimulation induced an activation of classical and non-classical NF?B signaling. The expression of LT?R-like immunoreactivity in GFAP+/Sox2+ NSCs was identified in well-established neurogenic zones of adult mouse brain. Quantitative RT-PCR and Western blot analysis validated the expression of LT?R in cultured NSCs/NPCs and brain neurogenic regions. LT?R expression was significantly increased during neural induction. LT?1?2 stimulation in cultured NSCs/NPCs promoted astroglial and oligodendrocytic lineage differentiation, but inhibited neuronal lineage differentiation. Astroglial NF?B inactivation in GFAP-dnI?B? transgenic mice rescued LT?R-mediated abnormal phenotypes of cultured NSCs/NPCs. CONCLUSION:This study provides the first evidence for the expression and function of LT?R signaling in NSCs/NPCs. Activation of LT?R signaling promotes glial lineage differentiation. Our results suggest that neurogenesis is regulated by the adaptive immunity and inflammatory responses.

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Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells.

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Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells.

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