Pharmacologic inhibition of reactive gliosis blocks TNF-α-mediated neuronal apoptosis.
Reactive gliosis is an early pathological feature common to most neurodegenerative diseases, yet its regulation and impact remain poorly understood. Normally astrocytes maintain a critical homeostatic balance. After stress or injury they undergo rapid parainflammatory activation, characterized by hypertrophy, and increased polymerization of type III intermediate filaments (IFs), particularly glial fibrillary acidic protein and vimentin. However, the consequences of IF dynamics in the adult CNS remains unclear, and no pharmacologic tools have been available to target this mechanism in vivo. The mammalian retina is an accessible model to study the regulation of astrocyte stress responses, and their influence on retinal neuronal homeostasis. In particular, our work and others have implicated p38 mitogen-activated protein kinase (MAPK) signaling as a key regulator of glutamate recycling, antioxidant activity and cytokine secretion by astrocytes and related Müller glia, with potent influences on neighboring neurons. Here we report experiments with the small molecule inhibitor, withaferin A (WFA), to specifically block type III IF dynamics in vivo. WFA was administered in a model of metabolic retinal injury induced by kainic acid, and in combination with a recent model of debridement-induced astrocyte reactivity. We show that WFA specifically targets IFs and reduces astrocyte and Müller glial reactivity in vivo. Inhibition of glial IF polymerization blocked p38 MAPK-dependent secretion of TNF-α, resulting in markedly reduced neuronal apoptosis. To our knowledge this is the first study to demonstrate that pharmacologic inhibition of IF dynamics in reactive glia protects neurons in vivo.
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.|School of Optometry, University of California at Berkeley, Berkeley, CA, USA.
Izhar
I
Livne-Bar
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Susy
S
Lam
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Darren
D
Chan
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Xiaoxin
X
Guo
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Idil
I
Askar
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Adrian
A
Nahirnyj
School of Optometry, University of California at Berkeley, Berkeley, CA, USA.
John G
JG
Flanagan
Department of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.|Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada.
Jeremy M
JM
Sivak
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D065306:Corneal Injuries; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology; D007382:Intermediate Filaments / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D055351:Retinal Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D054358:Withanolides / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; D048051:p38 Mitogen-Activated Protein Kinases; C009684:withaferin A; C093642:SB 203580
J Neurosci. 2001 May 1;21(9):3104-12
11312295
Int Immunopharmacol. 2011 Aug;11(8):1137-42
21396905
Am J Pathol. 2007 Jul;171(1):53-67
17591953
J Neurosci. 2000 Jul 1;20(13):5037-44
10864961
Hum Mol Genet. 2008 Jun 1;17(11):1540-55
18276609
Prog Brain Res. 2008;173:353-73
18929121
J Neurosci Res. 2007 Dec;85(16):3523-9
17526018
Neuropharmacology. 2014 Jan;76 Pt A:184-93
23831681
FASEB J. 2015 Dec;29(12):4815-28
26251181
Exp Eye Res. 2011 Jun;92(6):521-7
21501608
J Cell Biol. 2009 Dec 14;187(6):761-72
19951898
FASEB J. 2013 Jan;27(1):187-98
23038755
Diabetologia. 2011 Mar;54(3):690-8
21116609
Invest Ophthalmol Vis Sci. 2001 Jul;42(8):1787-94
11431443
Brain Res. 2011 Feb 10;1373:189-94
21138740
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1001-12
19244206
Glia. 2000 Sep;31(3):267-72
10941153
FASEB J. 2005 Aug;19(10):1280-9
16051695
Invest Ophthalmol Vis Sci. 2013 Jan 30;54(1):871-80
23364356
J Biol Chem. 2012 Jan 6;287(2):989-1006
22117063
Mol Cell Proteomics. 2012 Feb;11(2):M111.012302
22126795
J Neuroimmune Pharmacol. 2007 Jun;2(2):140-53
18040839
J Neurosci. 2009 Oct 14;29(41):12865-77
19828801
Science. 2001 Jan 26;291(5504):657-61
11158678
J Mol Neurosci. 2015 Mar;55(3):596-608
25172309
Neurosci Lett. 1983 Jan 31;35(1):1-6
6189033
J Mol Neurosci. 2013 Nov;51(3):639-46
23733254
PLoS One. 2011 Mar 31;6(3):e18305
21483783
Prog Retin Eye Res. 2012 Mar;31(2):152-81
22155051
Neurosci Lett. 2011 Sep 1;501(3):132-7
21777656
Prog Retin Eye Res. 2006 Jul;25(4):397-424
16839797
J Glaucoma. 2009 Jun-Jul;18(5):341-53
19525723
Glia. 2000 Oct;32(1):42-50
10975909
J Neurochem. 2012 Apr;121(1):4-27
22251135
PLoS One. 2013 Dec 23;8(12 ):e83049
24376630
Aging Dis. 2010 Dec;1(3):199-211
22720195
Neurobiol Dis. 2012 Jan;45(1):243-52
21867754
Neuron. 2012 Mar 8;73(5):886-901
22405200
J Biol Chem. 2013 Feb 8;288(6):3831-43
23264628
Lancet Neurol. 2008 Aug;7(8):742-55
18635022
J Neurosci. 2004 May 26;24(21):5016-21
15163694
Cancer Lett. 2013 Jun 28;334(1):101-8
22935676
Cell Death Differ. 2010 Nov;17(11):1751-9
20489729
J Neurosci. 2009 Apr 29;29(17):5536-45
19403821
PLoS One. 2012;7(6):e39065
22720028
J Neurosci. 2001 Aug 15;21(16):6147-58
11487638
Chem Biol. 2007 Jun;14(6):623-34
17584610
Neuroreport. 1996 Apr 26;7(6):1125-9
8817515
Biochem Pharmacol. 2012 Nov 15;84(10):1282-91
22981382
Brain Res. 1996 Jan 22;707(1):134-7
8866724
PLoS One. 2010 Apr 16;5(4):e10105
20419128
J Anat. 2007 Jan;210(1):54-65
17229283
J Neuroimmune Pharmacol. 2013 Mar;8(1):287-300
23233245
Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6639-51
20574020
Neurosci Res. 2011 Oct;71(2):107-13
21693140
J Exp Med. 2011 Nov 21;208(12):2429-47
22084410
Toxicol In Vitro. 1995 Aug;9(4):369-74
20650101
Nature. 2010 Nov 11;468(7321):232-43
21068832
Mol Vis. 2011;17:1901-8
21850164
Glia. 2005 Jun;50(4):427-34
15846805
Exp Neurol. 1995 Feb;131(2):211-20
7895822
J Cell Physiol. 2014 Oct;229(10):1484-93
24648251
Angiogenesis. 2004;7(2):115-22
15516832
Biochim Biophys Acta. 2014 Dec;1846(2):599-616
25286320
J Biol Chem. 2011 Dec 30;286(52):44965-75
22072717
J Neurosci. 2000 Dec 1;20(23):8693-700
11102475
Invest Ophthalmol Vis Sci. 2009 Oct;50(10):4941-8
19420345
Mol Biol Cell. 2014 Mar;25(6):776-90
24478454
Gut. 2013 May;62(5):695-707
22684479
Arch Ophthalmol. 2004 Sep;122(9):1348-56
15364715
Neuron. 2008 Nov 6;60(3):430-40
18995817
Neuropharmacology. 2015 Sep;96(Pt A):55-69
25446571
J Cereb Blood Flow Metab. 2002 Jun;22(6):631-47
12045661
Mol Neurobiol. 2005;31(1-3):3-16
15953808
J Neurosci. 1994 Feb;14(2):846-56
8301364
Prog Retin Eye Res. 2006 Sep;25(5):490-513
16962364
PLoS One. 2015 Jul 17;10(7):e0133399
26186445
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3817-22
20133718
J Neurosci. 1996 May 1;16(9):2945-55
8622125
Am J Pathol. 2014 Apr;184(4):1017-29
24508229
J Biol Chem. 2010 Mar 5;285(10):7657-69
20048155
J Neurosci Res. 2011 Jul;89(7):1018-30
21484851