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Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism
Author(s) -
Menzfeld Christiane,
John Michael,
van Rossum Denise,
Regen Tommy,
Scheffel Jörg,
Janova Hana,
Götz Alexander,
Ribes Sandra,
Nau Roland,
Borisch Angela,
Boutin Philippe,
Neumann Konstantin,
Bremes Vanessa,
Wienands Jürgen,
Reichardt Holger M.,
Lühder Fred,
Tischner Denise,
Waetzig Vicky,
Herdegen Thomas,
Teismann Peter,
Greig Iain,
Müller Michael,
Pukrop Tobias,
Mildner Alexander,
Kettenmann Helmut,
Brück Wolfgang,
Prinz Marco,
Rotshenker Shlomo,
Weber Martin S.,
Hanisch UweKarsten
Publication year - 2015
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.22803
Subject(s) - bruton's tyrosine kinase , experimental autoimmune encephalomyelitis , microglia , biology , tyrosine kinase , signal transduction , proinflammatory cytokine , neuroprotection , inflammation , immunology , microbiology and biotechnology , immune system , cytokine , cancer research , neuroscience
The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll‐like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR‐induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti‐inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN‐sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. GLIA 2015;63:1083–1099