Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

Christiane Menzfeld; Michael John; Denise van Rossum; Tommy Regen; Jörg Scheffel; Hana Janova; Alexander Götz; Sandra Ribes; Roland Nau; Angela Borisch; Philippe Boutin; Konstantin Neumann; Vanessa Bremes; Jürgen Wienands; Holger M Reichardt; Fred Lühder; Denise Tischner; Vicky Waetzig; Thomas Herdegen; Peter Teismann; Iain Greig; Michael Müller; Tobias Pukrop; Alexander Mildner; Helmut Kettenmann; Wolfgang Brück; Marco Prinz; Shlomo Rotshenker; Martin S Weber; Uwe-Karsten Hanisch

doi:10.1002/glia.22803

Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

Christiane Menzfeld, Michael John, Denise van Rossum, Tommy Regen, Jörg Scheffel, Hana Janova, Alexander Götz, Sandra Ribes, Roland Nau, Angela Borisch, Philippe Boutin, Konstantin Neumann, Vanessa Bremes, Jürgen Wienands, Holger M Reichardt, Fred Lühder, Denise Tischner, Vicky Waetzig, Thomas Herdegen, Peter TeismannIain Greig, Michael Müller, Tobias Pukrop, Alexander Mildner, Helmut Kettenmann, Wolfgang Brück, Marco Prinz, Shlomo Rotshenker, Martin S Weber, Uwe-Karsten Hanisch

Medical Sciences

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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.GLIA 2015.

Original language	English
Pages (from-to)	1083-1099
Number of pages	17
Journal	Glia
Volume	63
Issue number	6
Early online date	2 Mar 2015
DOIs	https://doi.org/10.1002/glia.22803
Publication status	Published - Jun 2015

Bibliographical note

© 2015 Wiley Periodicals, Inc.
Acknowledgement
Grant sponsor: State of Lower Saxony-Israel Research Cooperation; Grant number: ZN2035; Grant sponsor:German Research Council; Grant number: SFB/TRR43 and FOR1336; Grant sponsor: Parkinson UK; Grant number: K-1001; Grant sponsor: ProFutura Program (University of Gottingen); Grant sponsor: Else Kroner Fresenius Stiftung;Grant number: A69/2010; Grant sponsor: DFG; Grant number: WE 3547/4–1; Grant sponsor: US National Multiple Sclerosis Society; Grant numbers: NMSS; PP 1660. The authors thank Elke Pralle, Susanne Kiecke and Caroline Jaß (University of Gottingen) for excellent technical assistance.

Keywords

BTK
inflammation
microglia
multiple sclerosis
signaling
TLR

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Menzfeld et al_Manuscript_Ann Neurol_2014_06_30
This is the peer reviewed version of the following article: Menzfeld, C, John, M, van Rossum, D, Regen, T, Scheffel, J, Janova, H, Götz, A, Ribes, S, Nau, R, Borisch, A, Boutin, P, Neumann, K, Bremes, V, Wienands, J, Reichardt, HM, Lühder, F, Tischner, D, Waetzig, V, Herdegen, T, Teismann, P, Greig, I, Müller, M, Pukrop, T, Mildner, A, Kettenmann, H, Brück, W, Prinz, M, Rotshenker, S, Weber, MS & Hanisch, U-K 2015, 'Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism' Glia, vol 63, no. 6, pp. 1083-1099., which has been published in final form at 10.1002/glia.22803. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Accepted author manuscript, 9.34 MB

Iain Greig
Person: Academic, Academic Related - Research

Cite this

Menzfeld, C., John, M., van Rossum, D., Regen, T., Scheffel, J., Janova, H., Götz, A., Ribes, S., Nau, R., Borisch, A., Boutin, P., Neumann, K., Bremes, V., Wienands, J., Reichardt, H. M., Lühder, F., Tischner, D., Waetzig, V., Herdegen, T., ... Hanisch, U.-K. (2015). Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia, 63(6), 1083-1099. https://doi.org/10.1002/glia.22803

Menzfeld, C, John, M, van Rossum, D, Regen, T, Scheffel, J, Janova, H, Götz, A, Ribes, S, Nau, R, Borisch, A, Boutin, P, Neumann, K, Bremes, V, Wienands, J, Reichardt, HM, Lühder, F, Tischner, D, Waetzig, V, Herdegen, T, Teismann, P, Greig, I, Müller, M, Pukrop, T, Mildner, A, Kettenmann, H, Brück, W, Prinz, M, Rotshenker, S, Weber, MS & Hanisch, U-K 2015, 'Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism', Glia, vol. 63, no. 6, pp. 1083-1099. https://doi.org/10.1002/glia.22803

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title = "Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism",

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.GLIA 2015.",

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author = "Christiane Menzfeld and Michael John and {van Rossum}, Denise and Tommy Regen and J{\"o}rg Scheffel and Hana Janova and Alexander G{\"o}tz and Sandra Ribes and Roland Nau and Angela Borisch and Philippe Boutin and Konstantin Neumann and Vanessa Bremes and J{\"u}rgen Wienands and Reichardt, {Holger M} and Fred L{\"u}hder and Denise Tischner and Vicky Waetzig and Thomas Herdegen and Peter Teismann and Iain Greig and Michael M{\"u}ller and Tobias Pukrop and Alexander Mildner and Helmut Kettenmann and Wolfgang Br{\"u}ck and Marco Prinz and Shlomo Rotshenker and Weber, {Martin S} and Uwe-Karsten Hanisch",

note = "{\textcopyright} 2015 Wiley Periodicals, Inc. Acknowledgement Grant sponsor: State of Lower Saxony-Israel Research Cooperation; Grant number: ZN2035; Grant sponsor:German Research Council; Grant number: SFB/TRR43 and FOR1336; Grant sponsor: Parkinson UK; Grant number: K-1001; Grant sponsor: ProFutura Program (University of Gottingen); Grant sponsor: Else Kroner Fresenius Stiftung;Grant number: A69/2010; Grant sponsor: DFG; Grant number: WE 3547/4–1; Grant sponsor: US National Multiple Sclerosis Society; Grant numbers: NMSS; PP 1660. The authors thank Elke Pralle, Susanne Kiecke and Caroline Ja{\ss} (University of Gottingen) for excellent technical assistance.",

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T1 - Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

AU - Menzfeld, Christiane

AU - John, Michael

AU - van Rossum, Denise

AU - Regen, Tommy

AU - Scheffel, Jörg

AU - Janova, Hana

AU - Götz, Alexander

AU - Ribes, Sandra

AU - Nau, Roland

AU - Borisch, Angela

AU - Boutin, Philippe

AU - Neumann, Konstantin

AU - Bremes, Vanessa

AU - Wienands, Jürgen

AU - Reichardt, Holger M

AU - Lühder, Fred

AU - Tischner, Denise

AU - Waetzig, Vicky

AU - Herdegen, Thomas

AU - Teismann, Peter

AU - Greig, Iain

AU - Müller, Michael

AU - Pukrop, Tobias

AU - Mildner, Alexander

AU - Kettenmann, Helmut

AU - Brück, Wolfgang

AU - Prinz, Marco

AU - Rotshenker, Shlomo

AU - Weber, Martin S

AU - Hanisch, Uwe-Karsten

N1 - © 2015 Wiley Periodicals, Inc. Acknowledgement Grant sponsor: State of Lower Saxony-Israel Research Cooperation; Grant number: ZN2035; Grant sponsor:German Research Council; Grant number: SFB/TRR43 and FOR1336; Grant sponsor: Parkinson UK; Grant number: K-1001; Grant sponsor: ProFutura Program (University of Gottingen); Grant sponsor: Else Kroner Fresenius Stiftung;Grant number: A69/2010; Grant sponsor: DFG; Grant number: WE 3547/4–1; Grant sponsor: US National Multiple Sclerosis Society; Grant numbers: NMSS; PP 1660. The authors thank Elke Pralle, Susanne Kiecke and Caroline Jaß (University of Gottingen) for excellent technical assistance.

PY - 2015/6

Y1 - 2015/6

N2 - 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.

AB - 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.

KW - BTK

KW - inflammation

KW - microglia

KW - multiple sclerosis

KW - signaling

KW - TLR

U2 - 10.1002/glia.22803

DO - 10.1002/glia.22803

M3 - Article

C2 - 25731696

SN - 0894-1491

VL - 63

SP - 1083

EP - 1099

JO - Glia

JF - Glia

IS - 6

ER -

Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

Abstract

Bibliographical note

Keywords

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Iain Greig

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