Journal
GLIA
Volume 63, Issue 6, Pages 1083-1099Publisher
WILEY
DOI: 10.1002/glia.22803
Keywords
BTK; inflammation; microglia; multiple sclerosis; signaling; TLR
Categories
Funding
- State of Lower Saxony-Israel Research Cooperation [ZN2035]
- German Research Council [SFB/TRR43, FOR1336]
- Parkinson UK [K-1001]
- ProFutura Program (University of Gottingen)
- Else Kroner Fresenius Stiftung [A69/2010]
- DFG [WE 3547/4-1]
- US National Multiple Sclerosis Society [NMSS, PP 1660]
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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
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