Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism.
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.
Institute of Neuropathology, University of Göttingen, Germany.
Christiane
C
Menzfeld
Michael
M
John
Denise
D
van Rossum
Tommy
T
Regen
Jörg
J
Scheffel
Hana
H
Janova
Alexander
A
Götz
Sandra
S
Ribes
Roland
R
Nau
Angela
A
Borisch
Philippe
P
Boutin
Konstantin
K
Neumann
Vanessa
V
Bremes
Jürgen
J
Wienands
Holger M
HM
Reichardt
Fred
F
Lühder
Denise
D
Tischner
Vicky
V
Waetzig
Thomas
T
Herdegen
Peter
P
Teismann
Iain
I
Greig
Michael
M
Müller
Tobias
T
Pukrop
Alexander
A
Mildner
Helmut
H
Kettenmann
Wolfgang
W
Brück
Marco
M
Prinz
Shlomo
S
Rotshenker
Martin S
MS
Weber
Uwe-Karsten
UK
Hanisch
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006868:Hydrolysis; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D058504:Th17 Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology*
D016207:Cytokines; D007155:Immunologic Factors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018696:Neuroprotective Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C069028:AG 127; C000945:dicyanmethane; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse
BTK; TLR; inflammation; microglia; multiple sclerosis; signaling