title: Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis.
abstract: The chemokine fractalkine modulates microglial responses in neurodegenerative diseases, including tauopathies, but the mechanistic processes and their relevance in human brain pathologies is not yet known. Here, we show that hippocampal HT22 cells expressing human TAU(P301L) mutant protein produce fractalkine, which in microglia activates AKT, inhibits glycogen synthase kinase-3β and upregulates the transcription factor NRF2/NFE2L2 and its target genes including heme oxygenase 1. In a mouse model of tauopathy based on stereotaxic delivery in hippocampus of an adeno-associated viral vector for expression of TAU(P301L), we confirmed that tau-injured neurons express fractalkine. NRF2- and fractalkine receptor-knockout mice did not express heme oxygenase 1 in microglia and exhibited increased microgliosis and astrogliosis in response to neuronal TAU(P301L) expression, demonstrating a crucial role of the fractalkine/NRF2/heme oxygenase 1 pathway in attenuation of the pro-inflammatory phenotype. The hippocampus of patients with Alzheimer's disease also exhibits increased expression of fractalkine in TAU-injured neurons that recruit microglia. These events correlated with increased levels of NRF2 and heme oxygenase 1 proteins, suggesting an attempt of the diseased brain to limit microgliosis. Our combined results indicate that fractalkine mobilizes NRF2 to limit over-activation of microglia and identify this new target to control unremitting neuroinflammation in tauopathies.
authors.affiliation: 1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: Nadia G
authors.initials: NG
authors.lastname: Innamorato
authors.forename: Tomasz
authors.initials: T
authors.lastname: Jaworski
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D024801:Tauopathies / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
chemical_list: D054428:Chemokine CX3CL1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D051547:Heme Oxygenase-1
keywords: Alzheimer’s disease; adeno-associated virus; neuroimmunology; oxidative stress