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ERK1/2 and p38 MAP kinases control prion protein fragment 90–231‐induced astrocyte proliferation and microglia activation
Author(s) -
Thellung Stefano,
Villa Valentina,
Corsaro Alessandro,
Pellistri Francesca,
Venezia Valentina,
Russo Claudio,
Aceto Antonio,
Robello Mauro,
Florio Tullio
Publication year - 2007
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20559
Subject(s) - microbiology and biotechnology , microglia , biology , astrogliosis , p38 mitogen activated protein kinases , chemokine , ccl5 , astrocyte , kinase , neuroinflammation , mapk/erk pathway , mitogen activated protein kinase , neuroglia , neuroscience , biochemistry , immunology , inflammation , in vitro , central nervous system , cytotoxic t cell , il 2 receptor
Abstract Astrogliosis and microglial activation are a common feature during prion diseases, causing the release of chemoattractant and proinflammatory factors as well as reactive free radicals, involved in neuronal degeneration. The recombinant protease‐resistant domain of the prion protein (PrP90–231) displays in vitro neurotoxic properties when refolded in a β‐sheet‐rich conformer. Here, we report that PrP90–231 induces the secretion of several cytokines, chemokines, and nitric oxide (NO) release, in both type I astrocytes and microglial cells. PrP90–231 elicited in both cell types the activation of ERK1/2 MAP kinase that displays, in astrocytes, a rapid kinetics and a proliferative response. Conversely, in microglia, PrP90–231‐dependent MAP kinase activation was delayed and long lasting, inducing functional activation and growth arrest. In microglial cells, NO release, dependent on the expression of the inducible NO synthase (iNOS), and the secretion of the chemokine CCL5 were Ca 2+ dependent and under the control of the MAP kinases ERK1/2 and p38: ERK1/2 inhibition, using PD98059, reduced iNOS expression, while p38 blockade by PD169316 inhibited CCL5 release. In summary, we demonstrate that glial cells are activated by extracellular misfolded PrP90–231 resulting in a proliferative/secretive response of astrocytes and functional activation of microglia, both dependent on MAP kinase activation. In particular, in microglia, PrP90–231 activated a complex signalling cascade involved in the regulation of NO and chemokine release. These data argue in favor of a causal role for misfolded prion protein in sustaining glial activation and, possibly, glia‐mediated neuronal death. © 2007 Wiley‐Liss, Inc.