INVESTIGADORES
RAMOS Alberto Javier
congresos y reuniones científicas
Título:
S100B IS A DAMAGE ASSOCIATED MOLECULAR PATTERN PROTEIN (DAMP) THAT PROMOTES REACTIVE GLIOSIS IN A RAGE DEPENDENT MANNER
Autor/es:
RAMOS AJ; ALEJANDRO VILLARREAL, ROCIO SEOANE, AGUSTINA GONZÁLEZ TORRES, MARIA FLORENCIA ANGELO, ROLANDO X. AVILES REYES, ALICIA ROSSI AND PHILIP A. BARKER
Lugar:
Cancun/Merida
Reunión:
Congreso; ISN-ASN Meeting /Glia Satellite Meeting in the context of the ISN-ASN Cancun; 2013
Institución organizadora:
International Society for Neurochemistry
Resumen:
Background: After brain injury, S100B extracellular level dramatically increases due
to active release from astrocytes and passive release from dying glia behaving as a
DAMP protein. Extracellular S100B induces astroglial secretion of pro-inflammatory
mediators and actives microglia. S100B binds to the Receptor for Advanced
Glycation End products (RAGE). RAGE downstream signaling induces NF-ĸB
activity.
Objective: To analyze if S100B can induce astroglial changes towards a reactive
phenotype in vitro and in vivo.
Methods: Primary cortical astrocytes were transfected with different plasmids
encoding RAGE, DN-RAGE, or RhoGTPases, and exposed to S100B to perform
gain-loss of function studies. Astroglial morphology was studied by
immunocytochemistry and phalloidin staining. In vivo S100B was injected
intracortically to anaesthetized male Wistar rats and brain sections were evaluated by
vimentin and GFAP immunostaining.
Results: S100B nanomolar or micromolar levels induced RAGE-dependent astroglial
hypertrophy, increased cell division showed by BrdU as well as the induction of a
migratory phenotype in astrocytes subjected to artificial injury by scratch wound
healing assays. Hypertrophy and migratory facilitation induced by S100B were
blocked by transfecting dominant negative forms of small RhoGTPases Rac-1 and
Cdc-42 or DN-RAGE. In addition, S100B exposure facilitates astrocytic survival to
oxidative stress induced by H2O2, an effect abolished by Erk, Akt but not by NF-kB
blockage. S100B also activates NF-ĸB transcriptional activity and RAGE promoter in
a dose-dependent manner in reporter studies. S100B augmented endogenous RAGE
expression, an effect partially prevented by NF-ĸB blockage or the expression of a
dominant negative Sp1. In vivo, intracerebral infusion of S100B is enough to induce
an astroglial reactive phenotype with increased vimentin and GFAP expression in
normal brains.
Conclusions: These findings demonstrate that S100B/RAGE induces phenotypic
changes in astrocytes similar to those observed during reactive gliosis in vitro. In
agreement with its role as a DAMP, extracellular S100B activates different RAGEdependent
signaling cascades that may support a feed-forward autocrine loop that
promotes inflammation in the injured brain. Supported by: UBACYT, PIP CONICET
1728, PICT 2008-1590