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 & 10 others Iain Greig, Michael Müller, Tobias Pukrop, Alexander Mildner, Helmut Kettenmann, Wolfgang Brück, Marco Prinz, Shlomo Rotshenker, Martin S Weber, Uwe-Karsten Hanisch

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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 languageEnglish
Pages (from-to)1083-1099
Number of pages17
JournalGlia
Volume63
Issue number6
Early online date2 Mar 2015
DOIs
Publication statusPublished - Jun 2015

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Tyrphostins
Inflammation
Toll-Like Receptors
Autoimmune Experimental Encephalomyelitis
Microglia
Protein-Tyrosine Kinases
Protein Kinase Inhibitors
Myelin Sheath
Neuroprotection
AG 127
Multiple Sclerosis
Hydrolysis
B-Lymphocytes
Anti-Inflammatory Agents
Cytokines

Keywords

  • BTK
  • inflammation
  • microglia
  • multiple sclerosis
  • signaling
  • TLR

Cite this

Menzfeld, C., John, M., van Rossum, D., Regen, T., Scheffel, J., Janova, H., ... 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

Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. / 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, Uwe-Karsten.

In: Glia, Vol. 63, No. 6, 06.2015, p. 1083-1099.

Research output: Contribution to journalArticle

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
Menzfeld C, John M, van Rossum D, Regen T, Scheffel J, Janova H et al. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia. 2015 Jun;63(6):1083-1099. https://doi.org/10.1002/glia.22803
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, Uwe-Karsten. / Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. In: Glia. 2015 ; Vol. 63, No. 6. pp. 1083-1099.
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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.",
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AU - Menzfeld, Christiane

AU - John, Michael

AU - van Rossum, Denise

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AU - Janova, Hana

AU - Götz, Alexander

AU - Ribes, Sandra

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AU - Borisch, Angela

AU - Boutin, Philippe

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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.

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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.

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KW - microglia

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KW - signaling

KW - TLR

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EP - 1099

JO - Glia

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