Alzheimer's disease; Huntington's disease; Parkinson's disease; Toll-like receptors; amyotrophic lateral sclerosis; inflammasomes; neuroinflammation; Alzheimer Disease/immunology; Amyotrophic Lateral Sclerosis/immunology; Humans; Huntington Disease/immunology; Immunity, Innate/immunology; Inflammation/immunology; Microglia/immunology; Neurodegenerative Diseases/immunology; Parkinson Disease/immunology; Immunity, Innate; Inflammation; Microglia; Neurodegenerative Diseases; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology; General Medicine
Abstract :
[en] The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.
Disciplines :
Neurology
Author, co-author :
Labzin, Larisa I; Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom, email: llabzin@mrc-lmb.cam.ac.uk
HENEKA, Michael ; Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology, University Hospitals Bonn, Bonn 53127, Germany, email: Michael.Heneka@ukb.uni-bonn.de ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA ; German Center for Neurodegenerative Diseases, Bonn 53175, Germany
Latz, Eicke; Institute of Innate Immunity, University Hospitals Bonn, Bonn 53127, Germany, email: eicke.latz@uni-bonn.de ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA ; German Center for Neurodegenerative Diseases, Bonn 53175, Germany ; Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway
Eicke Latz is supported by grants from the Deutsche Forschungsgemeinschaft (SFBs 670, 704, 1123; TRRs 57, 83; Exc 1023 and SPP1923), the ERC consolidator grant InflammAct and by the National Institutes of Health (RO1 HL112661). Larisa I. Labzin is supported by an EMBO Long-Term Postdoctoral Fellowship (ALTF1487–2015) and an Australian NHMRC Early Career Fellowship (CJ Martin) (GNT1124162). Michael T. Heneka is supported by Exc 1023, the SFB 1089 and the EU-JPND consortia InCure, TracInflamm and MADGIC.
Dugger BN, Dickson DW. 2017. Pathology of neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 9(7):a028035
Goedert M, Masuda-Suzukake M, Falcon B. 2017. Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 140:266-78
Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8(6):595-608
Wyss-Coray T. 2016. Ageing, neurodegeneration and brain rejuvenation. Nature 539(7628):180-86
Martin P, Wimo A, Guerchet M, et al. 2015. World Alzheimer report 2015: the global impact of dementia. Alzheimer's Disease Int. (ADI), London. http://www.alz.co.uk/worldreport2015
Massano J, Bhatia KP. 2012. Clinical approach to Parkinson's disease: features, diagnosis, and principles of management. Cold Spring Harb. Perspect. Med. 2(6):a008870-70
Kalia LV, Lang AE. 2015. Parkinson's disease. Lancet 386(9996):896-912
Sibilla C, Bertolotti A. 2017. Prion properties of SOD1 in amyotrophic lateral sclerosis and potential therapy. Cold Spring Harb. Perspect. Biol. 9(10):a024141
Waisman A, Ginhoux F, Greter M, Bruttger J. 2015. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 36(10):625-36
Lavin Y,Winter D, Blecher-Gonen R, et al. 2014. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159(6):1312-26
Ginhoux F, Greter M, Leboeuf M, et al. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841-45
Ajami B, Bennett JL, Krieger C, et al. 2007. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10(12):1538-43
Stevens B, Allen NJ, Vazquez LE, et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131(6):1164-78
Paolicelli RC, Bolasco G, Pagani F, et al. 2011. Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456-58
Fourgeaud L, Través PG, Tufail Y, et al. 2016. TAM receptors regulate multiple features of microglial physiology. Nature 532 (7598):240-44
Parkhurst CN, Yang G, Ninan I, et al. 2013. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596-609
Colonna M, Butovsky O. 2017. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35:441-68
Srinivasan K, Friedman BA, Larson JL, et al. 2016. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7:11295
Heneka MT, Kummer MP, Latz E. 2014. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14(7):463-77
Crotti A, Glass CK. 2015. The choreography of neuroinflammation in Huntington's disease. Trends Immunol. 36(6):364-73
Davalos D, Grutzendler J, Yang G, et al. 2005. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8(6):752-58
Freeman L, Guo H, David CN, et al. 2017. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J. Exp. Med. 214(5):1351-70
Kigerl KA, de Rivero Vaccari JP, Dietrich WD, et al. 2014. Pattern recognition receptors and central nervous system repair. Exp. Neurol. 258:5-16
De Nardo D. 2015. Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine 74(2):181-89
Latz E, Xiao TS, Stutz A. 2013. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13(6):397-411
Cox DJ, Field RH, Williams DG, et al. 2015. DNA sensors are expressed in astrocytes and microglia in vitro and are upregulated during gliosis in neurodegenerative disease. Glia 63(5):812-25
Yan SD, Chen X, Fu J, et al. 1996. RAGE and amyloid-βpeptide neurotoxicity in Alzheimer's disease. Nature 382(6593):685-91
Deane R, Singh I, Sagare AP, et al. 2012. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Investig. 122(4):1377-92
El Khoury JB, MooreKJ, MeansTK, et al. 2003. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med. 197(12):1657-66
Stewart CR, Stuart LM, Wilkinson K, et al. 2010. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11(2):155-61
Sheedy FJ, Grebe A, Rayner KJ, et al. 2013. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14(8):812-20
Halle A, Hornung V, Petzold GC, et al. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9(8):857-65
Heneka MT,KummerMP, Stutz A, et al. 2013. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674-78
Saresella M, La Rosa F, Piancone F, et al. 2016. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease. Mol. Neurodegener. 11:23-17
Dempsey C, Rubio Araiz A, Bryson KJ, et al. 2017. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-βand cognitive function in APP/PS1 mice. Brain Behav. Immun. 61:306-16
Tan M-S, Tan L, Jiang T, et al. 2014. Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. Cell Death Disease 5(8):e1382-12
Kaushal V, DyeR, Pakavathkumar P, et al. 2015. Neuronal NLRP1 inflammasome activation of Caspase-1 co-ordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 22(10):1676-86
Shaftel SS, Griffin WST, O'Banion MK. 2008. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J. Neuroinflamm. 5:7
Adamczak SE, de Rivero Vaccari JP, Dale G, et al. 2014. Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J. Cereb. Blood Flow Metab. 34(4):621-29
Denes A, Coutts G, Lénárt N, et al. 2015. AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. PNAS 112(13):4050-55
Kim C, Ho D-H, Suk J-E, et al. 2013. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4:1562-12
Daniele SG, Beraud D, Davenport C, et al. 2015. Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal. 8(376):ra45
Gustot A, Gallea JI, Sarroukh R, et al. 2015. Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease. Biochem. J. 471(3):323-33
Fellner L, Irschick R, Schanda K, et al. 2012. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61(3):349-60
Noelker C, Morel L, Lescot T, et al. 2013. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci. Rep. 3:1393
Codolo G, Plotegher N, Pozzobon T, et al. 2013. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLOS ONE 8(1):e55375-12 www.annualreviews.org Innate Immunity and Neurodegeneration 447
Gustin A, Kirchmeyer M, Koncina E, Felten P. 2015. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLOS ONE 10(6):e0130624
Zhou Y, Lu M, Du R-H, et al. 2016. MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease. Mol. Neurodegener. 11:28-43
Yan Y, Jiang W, Liu L, et al. 2015. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160(1-2):62-73
Zhao W, Beers DR, Bell S, et al. 2015. TDP-43 activates microglia through NF-κB and NLRP3 inflammasome. Exp. Neurol. 273:24-35
Meissner F, Molawi K, Zychlinsky A. 2010. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. PNAS 107(29):13046-50
Maier A, Deigendesch N, Müller K, et al. 2015. Interleukin-1 antagonist anakinra in amyotrophic lateral sclerosis-A pilot study. PLOS ONE 10(10):e0139684
Crotti A, BennerC,KermanBE, et al. 2014. Mutant huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat. Neurosci. 17(4):513-21
ZilkaN, Kazmerova Z, Jadhav S, et al. 2012. Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J. Neuroinflamm. 9:47-58
BlockML, Zecca L, Hong J-S. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8(1):57-69
Heneka MT, Carson MJ, Khoury El J, et al. 2015. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14(4):388-405
Guillot-Sestier M-V, Doty KR, Town T. 2015. Innate immunity fights Alzheimer's disease. Trends Neurosci. 38(11):674-81
Hickman SE, Allison EK, El Khoury J. 2008. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28(33):8354-60
Hong S, Beja-Glasser VF, Nfonoyim BM, et al. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352(6286):712-16
Colonna M, Wang Y. 2016. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17(4):201-7
Turnbull IR, Gilfillan S, Cella M, et al. 2006. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177(6):3520-24
Hamerman JA, Jarjoura JR, Humphrey MB, et al. 2006. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J. Immunol. 177(4):2051-55
Bin Zhang, Gaiteri C, Bodea L-G, et al. 2013. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153(3):707-20
Jiang T, Tan L, Zhu X-C, et al. 2014. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mousemodel of Alzheimer's disease. Neuropsychopharmacology 39(13):2949-62
Jay TR, Miller CM, Cheng PJ, et al. 2015. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mousemodels. J. Exp. Med. 212(3):287-95
Wang Y, Cella M, Mallinson K, et al. 2015. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160(6):1061-71
Condello C, Yuan P, Schain A, Grutzendler J. 2015. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6:6176-28
Atagi Y, Liu C-C, Painter MM, et al. 2015. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290(43):26043-50
Bailey CC, DeVaux LB, Farzan M. 2015. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290(43):26033-42
Mosher KI,Wyss-Coray T. 2014. Microglial dysfunction in brain aging and Alzheimer's disease. Biochem. Pharmacol. 88(4):594-604
Perry VH,HolmesC. 2014. Microglial priming in neurodegenerative disease. Nat. Rev.Neurol. 10(4):217-24
Netea MG, Joosten LAB, Latz E, et al. 2016. Trained immunity: a program of innate immune memory in health and disease. Science 352(6284):aaf1098-98
Tang Y, Li T, Li J, et al. 2014. Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson's disease. Cell Death Differ. 21(3):369-80
Gjoneska E, Pfenning AR, Mathys H, et al. 2015. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature 518(7539):365-69
CunninghamC. 2013. Microglia and neurodegeneration: the role of systemic inflammation. Glia 61(1):71-90
Erny D, Hrabě de Angelis AL, Jaitin D, et al. 2015. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18(7):965-77
Braniste V, Al-Asmakh M, Kowal C, et al. 2014. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6(263):ra158-58
Lee-Kirsch MA. 2017. The type I interferonopathies. Annu. Rev. Med. 68:297-315
Baruch K, Deczkowska A, David E, et al. 2014. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346(6205):89-93
