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Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

Item Type:Article
Title:Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism
Creators Name:Menzfeld, C. and John, M. and van Rossum, D. and Regen, T. and Scheffel, J. and Janova, H. and Götz, A. and Ribes, S. and Nau, R. and Borisch, A. and Boutin, P. and Neumann, K. and Bremes, V. and Wienands, J. and Reichardt, H.M. and Lühder, F. and Tischner, D. and Waetzig, V. and Herdegen, T. and Teismann, P. and Greig, I. and Müller, M. and Pukrop, T. and Mildner, A. and Kettenmann, H. and Brück, W. and Prinz, M. and Rotshenker, S. and Weber, M.S. and Hanisch, U.K.
Abstract: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.
Keywords:BTK, Inflammation, Microglia, Multiple Sclerosis, Signaling, TLR, Animals, Mice
Page Range:1083-1099
Date:June 2015
Additional Information:Copyright © 2015 Wiley Periodicals, Inc.
Official Publication:https://doi.org/10.1002/glia.22803
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