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dc.contributor.author
Rosciszewski, Gerardo Ariel
dc.contributor.author
Cadena, María Vanesa
dc.contributor.author
Murta, Verónica
dc.contributor.author
Lukin, Jeronimo
dc.contributor.author
Villarreal, Alejandro
dc.contributor.author
Roger, Thierry
dc.contributor.author
Ramos, Alberto Javier
dc.date.available
2018-06-04T16:52:51Z
dc.date.issued
2017-05
dc.identifier.citation
Rosciszewski, Gerardo Ariel; Cadena, María Vanesa; Murta, Verónica; Lukin, Jeronimo; Villarreal, Alejandro; et al.; Toll-Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) Activation Balance Astrocyte Polarization into a Proinflammatory Phenotype; Springer; Molecular Neurobiology; 55; 5; 5-2017; 3875-3888
dc.identifier.issn
0893-7648
dc.identifier.uri
http://hdl.handle.net/11336/47142
dc.description.abstract
Astrocytes react to brain injury with a generic response known as reactive gliosis, which involves activation of multiple intracellular pathways including several that may be beneficial for neuronal survival. However, by unknown mechanisms, reactive astrocytes can polarize into a proinflammatory phenotype that induces neurodegeneration. In order to study reactive gliosis and astroglial polarization into a proinflammatory phenotype, we used cortical devascularization-induced brain ischemia in Wistar rats and primary astroglial cell cultures exposed to oxygen-glucose deprivation (OGD). We analyzed the profile of TLR4 expression and the consequences of its activation by gain- and loss-of-function studies, and the effects produced by the activation of triggering receptor expressed on myeloid cells-2 (TREM-2), a negative regulator of TLR4 signaling. Both OGD exposure on primary astroglial cell cultures and cortical devascularization brain ischemia in rats induced TLR4 expression in astrocytes. In vivo, astroglial TLR4 expression was specifically observed in the ischemic penumbra surrounding necrotic core. Functional studies showed that OGD increased the astroglial response to the TLR4 agonist lipopolysaccharide (LPS), and conversely, TLR4 knockout primary astrocytes had impaired nuclear factor kappa-B (NF-κB) activation when exposed to LPS. In gain-of-function studies, plasmid-mediated TLR4 over-expression exacerbated astroglial response to LPS as shown by sustained NF-κB activation and increased expression of proinflammatory cytokines IL-1β and TNFα. TREM-2 expression, although present in naïve primary astrocytes, was induced by OGD, LPS, or high-mobility group box 1 protein (HMGB-1) exposure. TREM-2 activation by antibody cross-linking or the overexpression of TREM-2 intracellular adaptor, DAP12, partially suppressed LPS-induced NF-κB activation in purified astrocytic cultures. In vivo, TREM-2 expression was observed in macrophages and astrocytes located in the ischemic penumbra. While TREM-2+ macrophages were abundant at 3 days post-lesion (DPL) in the ischemic core, TREM-2+ astrocytes persisted in the penumbra until 14DPL. This study demonstrates that TLR4 expression increases astroglial sensitivity to ligands facilitating astrocyte conversion towards a proinflammatory phenotype, and that astroglial TREM-2 modulates this response reducing the downstream NF-κB activation. Therefore, the availability of TLR4 and TREM-2 ligands in the ischemic environment may control proinflammatory astroglial conversion to the neurodegenerative phenotype.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Springer
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Astrocyte
dc.subject
Inflammation
dc.subject
Ischemia
dc.subject
Microglia
dc.subject
Nf-&Amp;Kappa;B
dc.subject
Reactive Gliosis
dc.subject
Tlr4
dc.subject
Trem-2
dc.subject.classification
Otras Ciencias Biológicas
dc.subject.classification
Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
Toll-Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) Activation Balance Astrocyte Polarization into a Proinflammatory Phenotype
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-01T19:21:07Z
dc.identifier.eissn
1559-1182
dc.journal.volume
55
dc.journal.number
5
dc.journal.pagination
3875-3888
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Nueva York
dc.description.fil
Fil: Rosciszewski, Gerardo Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
dc.description.fil
Fil: Cadena, María Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
dc.description.fil
Fil: Murta, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
dc.description.fil
Fil: Lukin, Jeronimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
dc.description.fil
Fil: Villarreal, Alejandro. University of Freiburg; Alemania. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Roger, Thierry. Universite de Lausanne; Suiza
dc.description.fil
Fil: Ramos, Alberto Javier. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina
dc.journal.title
Molecular Neurobiology
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1007/s12035-017-0618-z
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007%2Fs12035-017-0618-z


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