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Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

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Abstract

A growing body of evidence suggests that excessive microglial activation and pesticide exposure may be linked to the etiology of PD; however, the mechanisms involved remain elusive. Emerging evidence indicates that intracellular inflammasome complex namely NLRP3 complex is involved in the recognition and execution of host inflammatory response. Thus, in the present study, we investigated the hypothesis that NLRP3 inflammasome activation is linked to rotenone (ROT)-induced microglial activation which is dependent upon a priming stimulus by a pathogen-associated molecular pattern (PAMP) or damage associated molecular pattern (DAMP), respectively. Herein using both BV2 cells and primary microglial cells, we show that LPS priming and subsequent ROT stimulation enhanced NLRP3 inflammasome activation, c-Abl and PKCδ activation, mitochondrial dysfunction, NF-κB activation, and autophagic markers, while TFEB levels were decreased dramatically. Mechanistic studies revealed c-Abl acts as a proximal signal that exacerbated the activation of the afore mentioned markers. Intriguingly, siRNA-mediated depletion or pharmacological inhibition of c-Abl via dasatinib abrogated LPS and ROT-induced microglial activation response via attenuation of NLRP3 inflammasome activation, mitochondrial oxidative stress, and ALS dysfunction. Moreover, mitoTEMPO, a mitochondrial antioxidant, attenuated NLRP3 inflammasome activation effects via blockade of c-Abl and PKCδ activation. In LPS treated mice, dasatinib attenuated NLRP3 inflammasome activation, c-Abl and PKCδ activation; and sickness behavior. Together our findings identify an exaggerated ROS/c-Abl/NLRP3 signaling axis in the heightened microglial activation response evidenced in LPS-primed ROT-stimulated microglial cells and suggest that targeting c-Abl-regulated NLRP3 inflammasome signaling offers a novel therapeutic strategy for PD treatment.

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References

  • Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, Bosia A, Ghigo D (2003) Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 552:141–144

    Article  CAS  PubMed  Google Scholar 

  • Alvarez AR, Sandoval PC, Leal NR, Castro PU, Kosik KS (2004) Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species. Neurobiol Dis 17:326–336

    Article  CAS  PubMed  Google Scholar 

  • Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc) 70:200–214

    Article  CAS  Google Scholar 

  • Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J, Compan V, Barbera-Cremades M, Yague J, Ruiz-Ortiz E, Anton J, Bujan S, Couillin I, Brough D, Arostegui JI, Pelegrin P (2014) The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15:738–748

    Article  CAS  PubMed  Google Scholar 

  • Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V (2011) Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol 187:613–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benetti E, Chiazza F, Patel NS, Collino M (2013) The NLRP3 Inflammasome as a novel player of the intercellular crosstalk in metabolic disorders. Mediat Inflamm 2013:678627

    Google Scholar 

  • Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3:1301–1306

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature reviews 8:57–69

    Article  CAS  PubMed  Google Scholar 

  • Boaru SG, Borkham-Kamphorst E, Van de Leur E, Lehnen E, Liedtke C, Weiskirchen R (2015) NLRP3 inflammasome expression is driven by NF-kappaB in cultured hepatocytes. Biochem Biophys Res Commun 458:700–706

    Article  CAS  PubMed  Google Scholar 

  • Brahmachari S, Ge P, Lee SH, Kim D, Karuppagounder SS, Kumar M, Mao X, Shin JH, Lee Y, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM, Ko HS (2016) Activation of tyrosine kinase c-Abl contributes to alpha-synuclein-induced neurodegeneration. J Clin Invest 126:2970–2988

    Article  PubMed  PubMed Central  Google Scholar 

  • Brasher BB, Van Etten RA (2000) C-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines. J Biol Chem 275:35631–35637

    Article  CAS  PubMed  Google Scholar 

  • Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, Harapanhalli R, Saber H, Morse D, Bullock J, Men A, Noory C, Ramchandani R, Kenna L, Booth B, Gobburu J, Jiang X, Sridhara R, Justice R, Pazdur R (2008) Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 14:352–359

    Article  CAS  PubMed  Google Scholar 

  • Burm SM, Zuiderwijk-Sick EA, t Jong AE, van der Putten C, Veth J, Kondova I, Bajramovic JJ (2015) Inflammasome-induced IL-1beta secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases. J Neurosci 35:678–687

    Article  PubMed  CAS  Google Scholar 

  • Cancino GI, Toledo EM, Leal NR, Hernandez DE, Yevenes LF, Inestrosa NC, Alvarez AR (2008) STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's beta-amyloid deposits. Brain : a journal of neurology 131:2425–2442

    Article  Google Scholar 

  • Carrithers MD, Dib-Hajj S, Carrithers LM, Tokmoulina G, Pypaert M, Jonas EA, Waxman SG (2007) Expression of the voltage-gated sodium channel NaV1.5 in the macrophage late endosome regulates endosomal acidification. J Immunol 178:7822–7832

    Article  CAS  PubMed  Google Scholar 

  • Chakrabarti A, Banerjee S, Franchi L, Loo YM, Gale M Jr, Nunez G, Silverman RH (2015) RNase L activates the NLRP3 inflammasome during viral infections. Cell Host Microbe 17:466–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang CY, Choi DK, Lee DK, Hong YJ, Park EJ (2013) Resveratrol confers protection against rotenone-induced neurotoxicity by modulating myeloperoxidase levels in glial cells. PLoS One 8:e60654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chao CC, Hu S, Peterson PK (1995) Glia, cytokines, and neurotoxicity. Crit Rev Neurobiol 9:189–205

    CAS  PubMed  Google Scholar 

  • Charli A, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG (2016) Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model. Neurotoxicology 53:302–313

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Na R, Boldt E, Ran Q (2015) NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure. Neurobiol Aging 36:2533–2543

    Article  CAS  PubMed  Google Scholar 

  • Chipuk JE, Bouchier-Hayes L, Green DR (2006) Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396–1402

    Article  CAS  PubMed  Google Scholar 

  • Chuang SY, Yang CH, Chou CC, Chiang YP, Chuang TH, Hsu LC (2013) TLR-induced PAI-2 expression suppresses IL-1beta processing via increasing autophagy and NLRP3 degradation. Proc Natl Acad Sci U S A 110:16079–16084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE, Le A, Ivanov N, Sopher BL, Carromeu C, Muotri AR, Garden GA, La Spada AR (2014) Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat Neurosci 17:1180–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A (2013) TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc Natl Acad Sci U S A 110:E1817–E1826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhawan G, Combs CK (2012) Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer's disease. J Neuroinflammation 9:117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhawan G, Floden AM, Combs CK (2012) Amyloid-beta oligomers stimulate microglia through a tyrosine kinase dependent mechanism. Neurobiol Aging 33:2247–2261

    Article  CAS  PubMed  Google Scholar 

  • Dorey K, Engen JR, Kretzschmar J, Wilm M, Neubauer G, Schindler T, Superti-Furga G (2001) Phosphorylation and structure-based functional studies reveal a positive and a negative role for the activation loop of the c-Abl tyrosine kinase. Oncogene 20:8075–8084

    Article  CAS  PubMed  Google Scholar 

  • Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esparza-Lopez J, Medina-Franco H, Escobar-Arriaga E, Leon-Rodriguez E, Zentella-Dehesa A, Ibarra-Sanchez MJ (2013) Doxorubicin induces atypical NF-kappaB activation through c-Abl kinase activity in breast cancer cells. J Cancer Res Clin Oncol 139:1625–1635

    Article  CAS  PubMed  Google Scholar 

  • Estrada LD, Zanlungo SM, Alvarez AR (2011) C-Abl tyrosine kinase signaling: a new player in AD tau pathology. Curr Alzheimer Res 8:643–651

    Article  CAS  PubMed  Google Scholar 

  • Estrada LD, Chamorro D, Yanez MJ, Gonzalez M, Leal N, von Bernhardi R, Dulcey AE, Marugan J, Ferrer M, Soto C, Zanlungo S, Inestrosa NC, Alvarez AR (2016) Reduction of Blood amyloid-beta oligomers in Alzheimer's disease transgenic mice by c-Abl kinase inhibition. J Alzheimer’s Dis: JAD 54:1193–1205

    Article  CAS  PubMed  Google Scholar 

  • Ferger AI, Campanelli L, Reimer V, Muth KN, Merdian I, Ludolph AC, Witting A (2010) Effects of mitochondrial dysfunction on the immunological properties of microglia. J Neuroinflammation 7:45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ferrari CC, Tarelli R (2011) Parkinson's disease and systemic inflammation. Parkinsons Dis 2011:436813

    PubMed  PubMed Central  Google Scholar 

  • Gao HM, Hong JS, Zhang W, Liu B (2002a) Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22:782–790

    CAS  PubMed  Google Scholar 

  • Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002b) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease. J Neurochem 81:1285–1297

    Article  CAS  PubMed  Google Scholar 

  • Gao HM, Hong JS, Zhang W, Liu B (2003) Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease. J Neurosci 23:1228–1236

    CAS  PubMed  Google Scholar 

  • Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS (2011) Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease. Environ Health Perspect 119:807–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao F, Chen D, Hu Q, Wang G (2013) Rotenone directly induces BV2 cell activation via the p38 MAPK pathway. PLoS One 8:e72046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 104:18754–18759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh A, Chandran K, Kalivendi SV, Joseph J, Antholine WE, Hillard CJ, Kanthasamy A, Kalyanaraman B (2010) Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model. Free Radic Biol Med 49:1674–1684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh A, Saminathan H, Kanthasamy A, Anantharam V, Jin H, Sondarva G, Harischandra DS, Qian Z, Rana A, Kanthasamy AG (2013) The peptidyl-prolyl isomerase Pin1 up-regulation and proapoptotic function in dopaminergic neurons: relevance to the pathogenesis of Parkinson disease. J Biol Chem 288:21955–21971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonfloni S, Maiani E, Di Bartolomeo C, Diederich M, Cesareni G (2012) Oxidative stress, DNA damage, and c-Abl signaling: at the crossroad in neurodegenerative diseases? International journal of cell biology 2012:683097

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gordon R, Hogan CE, Neal ML, Anantharam V, Kanthasamy AG, Kanthasamy A (2011) A simple magnetic separation method for high-yield isolation of pure primary microglia. J Neurosci Methods 194:287–296

    Article  PubMed  Google Scholar 

  • Gordon R, Singh N, Lawana V, Ghosh A, Harischandra DS, Jin H, Hogan C, Sarkar S, Rokad D, Panicker N, Anantharam V, Kanthasamy AG, Kanthasamy A (2016) Protein kinase Cdelta upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease. Neurobiol Dis 93:96–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C (2015) NLRP3 Inflammasome is expressed and functional in mouse Brain microglia but not in astrocytes. PLoS One 10:e0130624

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hebron ML, Lonskaya I, Moussa CE (2013a) Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Hum Mol Genet 22:3315–3328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hebron ML, Lonskaya I, Moussa CE (2013b) Tyrosine kinase inhibition facilitates autophagic SNCA/alpha-synuclein clearance. Autophagy 9:1249–1250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC, Salter RD (2013) Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J Immunol 191:5230–5238

    Article  CAS  PubMed  Google Scholar 

  • Hu W, Lu S, McAlpine I, Jamieson JD, Lee DU, Marroquin LD, Heyen JR, Jessen BA (2012) Mechanistic investigation of imatinib-induced cardiac toxicity and the involvement of c-Abl kinase. Toxicol Sci 129:188–199

    Article  CAS  PubMed  Google Scholar 

  • Imam SZ, Zhou Q, Yamamoto A, Valente AJ, Ali SF, Bains M, Roberts JL, Kahle PJ, Clark RA, Li S (2011) Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease. J Neurosci 31:157–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Indo HP, Davidson M, Yen HC, Suenaga S, Tomita K, Nishii T, Higuchi M, Koga Y, Ozawa T, Majima HJ (2007) Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7:106–118

    Article  CAS  PubMed  Google Scholar 

  • Ippagunta SK, Brand DD, Luo J, Boyd KL, Calabrese C, Stienstra R, Van de Veerdonk FL, Netea MG, Joosten LA, Lamkanfi M, Kanneganti TD (2010) Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis. J Biol Chem 285:12454–12462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL, Sutterwala FS (2013) Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39:311–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A 106:14063–14068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang Y, Lee AY, Jeong SH, Park KH, Paik MK, Cho NJ, Kim JE, Cho MH (2015) Chlorpyrifos induces NLRP3 inflammasome and pyroptosis/apoptosis via mitochondrial oxidative stress in human keratinocyte HaCaT cells. Toxicology 338:37–46

    Article  CAS  PubMed  Google Scholar 

  • Javed H, Azimullah S, Haque ME, Ojha SK (2016) Cannabinoid type 2 (CB2) receptors activation protects against oxidative stress and Neuroinflammation associated dopaminergic Neurodegeneration in rotenone model of Parkinson's disease. Front Neurosci 10:321

    Article  PubMed  PubMed Central  Google Scholar 

  • Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, Morrison JP, Chen VS, Gris D, Matsushima GK, Ting JP (2010) The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci 30:15811–15820

    Article  CAS  PubMed  Google Scholar 

  • Jin H, Kanthasamy A, Harischandra DS, Kondru N, Ghosh A, Panicker N, Anantharam V, Rana A, Kanthasamy AG (2014) Histone hyperacetylation up-regulates protein kinase Cdelta in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease. J Biol Chem 289:34743–34767

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jing Z, Caltagarone J, Bowser R (2009) Altered subcellular distribution of c-Abl in Alzheimer's disease. J Alzheimers Dis 17:409–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, Quong AA, Latz E, Scott CP, Alnemri ES (2010) Anti-inflammatory compounds parthenolide and bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem 285:9792–9802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanthasamy A, Anantharam V, Ali SF, Kanthasamy AG (2006) Methamphetamine induces autophagy and apoptosis in a mesencephalic dopaminergic neuronal culture model: role of cathepsin-D in methamphetamine-induced apoptotic cell death. Ann N Y Acad Sci 1074:234–244

    Article  CAS  PubMed  Google Scholar 

  • Karin M (1999) How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 18:6867–6874

    Article  CAS  PubMed  Google Scholar 

  • Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS (2014) The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Scientific reports 4:4874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katsumata R, Ishigaki S, Katsuno M, Kawai K, Sone J, Huang Z, Adachi H, Tanaka F, Urano F, Sobue G (2012) C-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis. PloS one 7:e46185.

  • Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K (2012) Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells--implications for age-related macular degeneration (AMD). Immunol Lett 147:29–33

    Article  CAS  PubMed  Google Scholar 

  • Keeney PM, Xie J, Capaldi RA, Bennett JP Jr (2006) Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci 26:5256–5264

    Article  CAS  PubMed  Google Scholar 

  • Kesidou E, Lagoudaki R, Touloumi O, Poulatsidou KN, Simeonidou C (2013) Autophagy and neurodegenerative disorders. Neural Regen Res 8:2275–2283

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y, Stehlik C (2012) An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36:464–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med 38:333–347

    Article  CAS  PubMed  Google Scholar 

  • Kim MJ, Yoon JH, Ryu JH (2016) Mitophagy: a balance regulator of NLRP3 inflammasome activation. BMB Rep 49:529–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM (2010) Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A 107:16691–16696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Komatsu M, Ichimura Y (2010) Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 584:1374–1378

    Article  CAS  PubMed  Google Scholar 

  • Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15

    Article  CAS  PubMed  Google Scholar 

  • Latz E (2010) The inflammasomes: mechanisms of activation and function. Curr Opin Immunol 22:28–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lema Tome CM, Tyson T, Rey NL, Grathwohl S, Britschgi M, Brundin P (2013) Inflammation and alpha-synuclein's prion-like behavior in Parkinson's disease--is there a link? Mol Neurobiol 47:561–574

    Article  CAS  PubMed  Google Scholar 

  • Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278:8516–8525

    Article  CAS  PubMed  Google Scholar 

  • Lima H Jr, Jacobson LS, Goldberg MF, Chandran K, Diaz-Griffero F, Lisanti MP, Brojatsch J (2013) Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle 12:1868–1878

    Article  CAS  PubMed  Google Scholar 

  • Lin M, Chandramani-Shivalingappa P, Jin H, Ghosh A, Anantharam V, Ali S, Kanthasamy AG, Kanthasamy A (2012) Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells. Neuroscience 210:308–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lombardo LJ et al (2004) Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658–6661

    Article  CAS  PubMed  Google Scholar 

  • Lu W, Lee HK, Xiang C, Finniss S, Brodie C (2007) The phosphorylation of tyrosine 332 is necessary for the caspase 3-dependent cleavage of PKCdelta and the regulation of cell apoptosis. Cell Signal 19:2165–2173

    Article  CAS  PubMed  Google Scholar 

  • Mader BJ, Pivtoraiko VN, Flippo HM, Klocke BJ, Roth KA, Mangieri LR, Shacka JJ (2012) Rotenone inhibits autophagic flux prior to inducing cell death. ACS Chem Neurosci 3:1063–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahul-Mellier AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, Lamontanara AJ, Bisquertt A, Eliezer D, Masliah E, Halliday G, Hantschel O, Lashuel HA (2014) C-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson's disease. Hum Mol Genet 23:2858–2879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38:1285–1291

    Article  CAS  PubMed  Google Scholar 

  • McKnight NC, Zhenyu Y (2013) Beclin 1, an essential component and master regulator of PI3K-III in health and disease. Curr Pathobiol Rep 1:231–238

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitroulis I, Skendros P, Ritis K (2010) Targeting IL-1beta in disease; the expanding role of NLRP3 inflammasome. European journal of internal medicine 21:157–163

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N (2007a) Autophagy: process and function. Genes Dev 21:2861–2873

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N (2007b) The role of mammalian autophagy in protein metabolism. Proc Jpn Acad Ser B Phys Biol Sci 83:39–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moresco EM, Koleske AJ (2003) Regulation of neuronal morphogenesis and synaptic function by Abl family kinases. Curr Opin Neurobiol 13:535–544

    Article  CAS  PubMed  Google Scholar 

  • Moresco EM, Scheetz AJ, Bornmann WG, Koleske AJ, Fitzsimonds RM (2003) Abl family nonreceptor tyrosine kinases modulate short-term synaptic plasticity. J Neurophysiol 89:1678–1687

    Article  CAS  PubMed  Google Scholar 

  • Moriyama Y, Takano T, Ohkuma S (1982) Acridine orange as a fluorescent probe for lysosomal proton pump. J Biochem 92:1333–1336

    Article  CAS  PubMed  Google Scholar 

  • Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, oxidative stress and the pathogenesis of Parkinson's disease. Clin Neurosci Res 6:261–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230

    Article  CAS  PubMed  Google Scholar 

  • Ozaki E, Campbell M, Doyle SL (2015) Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res 8:15–27

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Pablos RM, Herrera AJ, Espinosa-Oliva AM, Sarmiento M, Munoz MF, Machado A, Venero JL (2014) Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation. J Neuroinflammation 11:34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Panicker N, Saminathan H, Jin H, Neal M, Harischandra DS, Gordon R, Kanthasamy K, Lawana V, Sarkar S, Luo J, Anantharam V, Kanthasamy AG, Kanthasamy A (2015) Fyn kinase regulates microglial Neuroinflammatory responses in cell culture and animal models of Parkinson's disease. J Neurosci 35:10058–10077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plaza Davila M, Martin Munoz P, Tapia JA, Ortega Ferrusola C, Balao da Silva CC, Pena FJ (2015) Inhibition of mitochondrial complex I leads to decreased motility and membrane integrity related to increased hydrogen peroxide and reduced ATP production, while the inhibition of glycolysis has less impact on sperm motility. PLoS One 10:e0138777

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Porkka K et al (2008) Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 112:1005–1012

    Article  CAS  PubMed  Google Scholar 

  • Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462

    Article  PubMed  PubMed Central  Google Scholar 

  • Rubartelli A (2014) DAMP-mediated activation of NLRP3-Inflammasome in Brain sterile inflammation: the fine line between healing and Neurodegeneration. Front Immunol 5:99

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268

    Article  CAS  PubMed  Google Scholar 

  • Sakurai H, Suzuki S, Kawasaki N, Nakano H, Okazaki T, Chino A, Doi T, Saiki I (2003) Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. J Biol Chem 278:36916–36923

    Article  CAS  PubMed  Google Scholar 

  • Salminen A, Ojala J, Kaarniranta K, Kauppinen A (2012) Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases. Cell Mol Life Sci 69:2999–3013

    Article  CAS  PubMed  Google Scholar 

  • Schlatterer SD, Acker CM, Davies P (2011a) c-Abl in neurodegenerative disease. J Mol Neurosci: MN 45:445–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlatterer SD, Tremblay MA, Acker CM, Davies P (2011b) Neuronal c-Abl overexpression leads to neuronal loss and neuroinflammation in the mouse forebrain. J Alzheimer’s Dis: JAD 25:119–133

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seo J, Ottesen EW, Singh RN (2014) Antisense methods to modulate pre-mRNA splicing. Methods Mol Biol 1126:271–283

    Article  CAS  PubMed  Google Scholar 

  • Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13:255–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shoji H, Watanabe M, Itoh S, Kuwahara H, Hattori F (1993) Japanese encephalitis and parkinsonism. J Neurol 240:59–60

    Article  CAS  PubMed  Google Scholar 

  • Siddiqui A, Bhaumik D, Chinta SJ, Rane A, Rajagopalan S, Lieu CA, Lithgow GJ, Andersen JK (2015) Mitochondrial quality control via the PGC1alpha-TFEB signaling pathway is compromised by Parkin Q311X mutation but independently restored by Rapamycin. J Neurosci 35:12833–12844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorbara MT, Girardin SE (2011) Mitochondrial ROS fuel the inflammasome. Cell Res 21:558–560

    Article  PubMed  PubMed Central  Google Scholar 

  • Stehlik C, Lee SH, Dorfleutner A, Stassinopoulos A, Sagara J, Reed JC (2003) Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. J Immunol 171:6154–6163

    Article  CAS  PubMed  Google Scholar 

  • Stuart JR, Kawai H, Tsai KK, Chuang EY, Yuan ZM (2005) C-Abl regulates early growth response protein (EGR1) in response to oxidative stress. Oncogene 24:8085–8092

    Article  CAS  PubMed  Google Scholar 

  • Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN (2013) The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153:348–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun X, Wu F, Datta R, Kharbanda S, Kufe D (2000) Interaction between protein kinase C delta and the c-Abl tyrosine kinase in the cellular response to oxidative stress. J Biol Chem 275:7470–7473

    Article  CAS  PubMed  Google Scholar 

  • Sutterwala FS, Haasken S, Cassel SL (2014) Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci 1319:82–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632

    Article  CAS  PubMed  Google Scholar 

  • Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107:7–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanida I, Ueno T, Kominami E (2008) LC3 and autophagy. Methods Mol Biol 445:77–88

    Article  CAS  PubMed  Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518

    Article  CAS  PubMed  Google Scholar 

  • Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomas-Camardiel M, Venero JL, Herrera AJ, De Pablos RM, Pintor-Toro JA, Machado A, Cano J (2005) Blood-brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: protective effect by estradiol treatment in ovariectomized animals. J Neurosci Res 80:235–246

    Article  CAS  PubMed  Google Scholar 

  • Tremblay MA, Acker CM, Davies P (2010) Tau phosphorylated at tyrosine 394 is found in Alzheimer's disease tangles and can be a product of the Abl-related kinase, Arg. J Alzheimers Dis 19:721–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31:16064–16069

    Article  CAS  PubMed  Google Scholar 

  • Tschopp J, Schroder K (2010) NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 10:210–215

    Article  CAS  PubMed  Google Scholar 

  • Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E, La Spada AR (2012) PGC-1alpha rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl med 4:142ra197.

  • van de Veerdonk FL, Netea MG, Dinarello CA, Joosten LA (2011) Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol 32:110–116

    Article  PubMed  CAS  Google Scholar 

  • Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G (2003) Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22:1313–1324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP (2011a) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen J, Ribeiro R, Zhang Y (2011b) Specific PKC isoforms regulate LPS-stimulated iNOS induction in murine microglial cells. J Neuroinflammation 8:38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Won JH, Park S, Hong S, Son S, Yu JW (2015) Rotenone-induced impairment of mitochondrial electron transport chain confers a selective priming signal for NLRP3 Inflammasome activation. J Biol Chem 290:27425–27437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu XF, Ouyang ZJ, Feng LL, Chen G, Guo WJ, Shen Y, Wu XD, Sun Y, Xu Q (2014) Suppression of NF-kappaB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. Toxicol Appl Pharmacol 281:146–156

    Article  CAS  PubMed  Google Scholar 

  • Wu F, Xu HD, Guan JJ, Hou YS, Gu JH, Zhen XC, Qin ZH (2015) Rotenone impairs autophagic flux and lysosomal functions in Parkinson's disease. Neuroscience 284:900–911

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Klionsky DJ (2009) An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335:1–32

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S, Weichselbaum R, Kufe D (1999) p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399:814–817

    Article  CAS  PubMed  Google Scholar 

  • Yuan YH, Sun JD, Wu MM, Hu JF, Peng SY, Chen NH (2013) Rotenone could activate microglia through NFkappaB associated pathway. Neurochem Res 38:1553–1560

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Beers DR, Bell S, Wang J, Wen S, Baloh RH, Appel SH (2015) TDP-43 activates microglia through NF-kappaB and NLRP3 inflammasome. Exp Neurol 273:24–35

    Article  CAS  PubMed  Google Scholar 

  • Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–140

    Article  CAS  PubMed  Google Scholar 

  • Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grant NS078247 and NS088206 (awarded to A.K). The Dean’s Professorship to A.K is also acknowledged. The W. Eugene and Linda Lloyd Endowed Chair to A.G.K. and Salisbury Chair to AK is also acknowledged.

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  1. Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA

    Vivek Lawana, Neeraj Singh, Souvarish Sarkar, Adhithiya Charli, Huajun Jin, Vellareddy Anantharam, Anumantha G. Kanthasamy & Arthi Kanthasamy

  2. Parkinson Disorders Research Laboratory, Department of Biomedical Sciences, 2016 Veterinary Medicine Building, Iowa State University, Ames, IA, 50011, USA

    Arthi Kanthasamy

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  1. Vivek Lawana
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  2. Neeraj Singh
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Lawana, V., Singh, N., Sarkar, S. et al. Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System. J Neuroimmune Pharmacol 12, 624–660 (2017). https://doi.org/10.1007/s11481-017-9746-5

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