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Cerebral Innate Immunity in Drosophila Melanogaster

Zilkha Neurogenetic Institute, Keck School of Medicine at the University of Southern California, Los Angeles, CA 90033, USA

Special Issues: What functional role do regional variations in microglia serve within the brain, for example in homeostasis?

Modeling innate immunity in Drosophila melanogaster has a rich history that includes ground-breaking discoveries in pathogen detection and signaling. These studies revealed the evolutionary conservation of innate immune pathways and mechanisms of pathogen detection, resulting in an explosion of findings in the innate immunity field. In D. melanogaster, studies have focused primarily on responses driven by the larval fat body and hemocytes, analogs to vertebrate liver and macrophages, respectively. Aside from pathogen detection, many recent mammalian studies associate innate immune pathways with development and disease pathogenesis. Importantly, these studies stress that the innate immune response is integral to maintain central nervous system (CNS) health. Microglia, which are the vertebrate CNS mononuclear phagocytes, drive vertebrate cerebral innate immunity. The invertebrate CNS contains microglial-like cells-ensheathing glia and reticular glia-that could be used to answer basic questions regarding the evolutionarily conserved innate immune processes in CNS development and health. A deeper understanding of the relationship between D. melanogaster phagocytic microglial-like cells and vertebrate microglia will be key to answering basic and translational questions related to cerebral innate immunity.
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Keywords Brain; Drosophila melanogaster; glia; microglia; neuroimmunology; neuroinflammation

Citation: Brian P. Leung, Kevin R. Doty, Terrence Town. Cerebral Innate Immunity in Drosophila Melanogaster. AIMS Neuroscience, 2015, 2(1): 35-51. doi: 10.3934/Neuroscience.2015.1.35


  • 1. O'Neill LAJ, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13: 453-460.    
  • 2. Janeway CA Jr, Medzhitov R (2002) Innate Immune Recognition. Annu Rev Immunol 20:197-216.    
  • 3. Lemaitre B, Nicolas E, Michaut L, et al. (1996) The Dorsoventral Regulatory Gene Cassette spätzle/Toll/cactus Controls the Potent Antifungal Response in Drosophila Adults. Cell 86:973-983.    
  • 4. Williams MJ (2007) Drosophila Hemopoiesis and Cellular Immunity. J Immunol 178:4711-4716.    
  • 5. Hoffmann JA, Reichhart J-M (2002) Drosophila innate immunity: an evolutionary perspective. Nat Immunol 3: 121-126.    
  • 6. Petersen AJ, Katzenberger RJ, Wassarman DA (2013) The Innate Immune Response Transcription Factor Relish Is Necessary for Neurodegeneration in a Drosophila Model of Ataxia-Telangiectasia. Genetics 194: 133-142.    
  • 8. Petersen AJ, Rimkus SA, Wassarman DA (2012) ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila. Proc Natl Acad Sci U S A 109: E656-E664.    
  • 9. Cao Y, Chtarbanova S, Petersen AJ, et al. (2013) Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain. Proc Natl Acad Sci U S A 110: E1752-E1760.    
  • 10. Freeman MR, doherty J (2006) Glial cell biology in Drosophila and vertebrates. Trends Neurosci 29: 82-90.    
  • 11. Eroglu C, Barres BA (2010) Regulation of synaptic connectivity by glia. Nature 468: 223-231.    
  • 12. Levashina EA, Moita LF, Blandin S, et al. (2001) Conserved Role of a Complement-like Protein in Phagocytosis Revealed by dsRNA Knockout in Cultured Cells of the Mosquito, Anopheles gambiae. Cell 104: 709-718.    
  • 13. Poltorak A (1998) Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene. Science 282: 2085-2088.
  • 14. Hartenstein V (2011) Morphological diversity and development of glia in Drosophila. Glia 59:1237-1252.    
  • 15. Awasaki T, Lai S-L, Ito K, et al. (2008) Organization and postembryonic development of glial cells in the adult central brain of Drosophila. J Neurosci 28: 13742-13753.    
  • 16. Jenett A, Rubin GM, Ngo T-TB, et al. (2012) A GAL4-Driver Line Resource for Drosophila Neurobiology. Cell Rep 2: 991-1001.    
  • 17. Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest122: 1164-1171.
  • 18. Kohl J, Jefferis GSXE (2011) Neuroanatomy: Decoding the Fly Brain. Curr Biol 21: R19-R20.    
  • 19. Butler AB, Hodos W (2005) Frontmatter: Evolution and Adaptation, 1 Eds. New Jersey/ Canada: John Wiley and Sons.
  • 20. Davis RL (2004) Olfactory learning. Neuron 44:31-48.    
  • 21. Sakano H (2014) Neural Map Formation in the Mouse Olfactory System. Neuron 67: 530-542.
  • 22. Yu H-H, Awasaki T, Schroeder MD, et al. (2013) Clonal Development and Organization of the Adult Drosophila Central Brain. Curr Biol 23: 633-643.    
  • 23. Rowitch DH, Kriegstein AR (2010) Developmental genetics of vertebrate glial-cell specification. Nature 468: 214-222.    
  • 24. Ou J, He Y, Xiao X, et al. (2014) Glial cells in neuronal development: recent advances and insights from Drosophila melanogaster. Neurosci Bull 30: 584-594.    
  • 25. Hakim Y, Yaniv SP, Schuldiner O (2014) Astrocytes Play a Key Role in Drosophila Mushroom Body Axon Pruning. PLoS ONE 9: e86178.    
  • 26. Edwards TN, Meinertzhagen IA (2010) The functional organisation of glia in the adult brain of Drosophila and other insects. Prog Neurobiol 90: 471-497.    
  • 27. Mayer F, Mayer N, Chinn L, et al. (2009) Evolutionary Conservation of Vertebrate Blood-Brain Barrier Chemoprotective Mechanisms in Drosophila. Journal of Neuroscience 29: 3538-3550.    
  • 28. Ito K, Awano W, Suzuki K, et al. (1997) The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. Development 124: 761-771.
  • 29. Crittenden JR, Skoulakis EMC, Han K-A, et al. (1998) Tripartite Mushroom Body Architecture Revealed by Antigenic Markers. Learn Mem 5: 38-51.
  • 30. Leiss F, Groh C, Butcher NJ, et al. (2009) Synaptic organization in the adult Drosophila mushroom body calyx. J Comp Neurol 517: 808-824.    
  • 31. Lawson LJ, Perry VH, Dri P, et al. (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39: 151-170.    
  • 32. Tremblay ME, Stevens B, Sierra A, et al. (2011) The Role of Microglia in the Healthy Brain. J Neurosci 31: 16064-16069.    
  • 33. Jinno S, Fleischer F, Eckel S, et al. (2007) Spatial arrangement of microglia in the mouse hippocampus: A stereological study in comparison with astrocytes. Glia 55: 1334-1347.    
  • 34. Jinno S, Kosaka T (2008) Reduction of Iba1-expressing microglial process density in the hippocampus following electroconvulsive shock. Exp Neurol 212: 440-447.    
  • 35. Coutinho-Budd J, Freeman MR (2013) Probing the enigma: unraveling glial cell biology in invertebrates. Curr Opin Neurobiol 23: 1073-1079.    
  • 36. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14: 1398-1405.    
  • 37. Stork T, Bernardos R, Freeman MR (2012) Analysis of Glial Cell Development and Function in Drosophila. Cold Spring Harb Protoc: 1-17.
  • 38. Bell RD, Winkler EA, Sagare AP, et al. (2010) Pericytes Control Key Neurovascular Functions and Neuronal Phenotype in the Adult Brain and during Brain Aging. Neuron 68: 409-427.    
  • 39. Barres BA (2008) The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease. Neuron 60:430-440.    
  • 40. Hall CN, Reynell C, Gesslein B, et al. (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55-60.    
  • 41. Stephan AH, Madison DV, Mateos JM, et al. (2013) A Dramatic Increase of C1q Protein in the CNS during Normal Aging. J Neurosci 33: 13460-13474.    
  • 42. Tasdemir-Yilmaz OE, Freeman MR (2014) Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev 28: 20-33.    
  • 43. Liu Z, Chen Y, Wang D, et al. (2010) Distinct Presynaptic and Postsynaptic Dismantling Processes of Drosophila Neuromuscular Junctions during Metamorphosis. J Neurosci 30:11624-11634.    
  • 44. Palgi M, Lindström R, Peränen J, et al. (2009) Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons. Proc Natl Acad Sci U S A 106:2429-2434.    
  • 45. Guillot-Sestier MV, Town T (2013) Innate Immunity in Alzheimer's Disease: A Complex Affair. CNS Neurol Disord Drug Targets 12: 1-14.    
  • 46. Gate D, Rezai-Zadeh K, Jodry D, et al. (2010) Macrophages in Alzheimer's disease: the blood-borne identity. J Neural Transm 117: 961-970.    
  • 47. Doherty J, Logan MA, Tasdemir OE, et al. (2009) Ensheathing Glia Function as Phagocytes in the Adult Drosophila Brain. J Neurosci 29: 4768-781.    
  • 48. Town T, Nikolic V, Tan J (2005) The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation 2: 24.    
  • 49. Aguzzi A, Barres BA, Bennett ML (2013) Microglia: Scapegoat, Saboteur, or Something Else? Science 339: 156-161.    
  • 50. Li Y, Du X-F, Liu C-S, et al. (2012) Reciprocal Regulation between Resting Microglial Dynamics and Neuronal Activity In Vivo. Dev Cell 23: 1189-1202.    
  • 51. Streit WJ (2006) Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosc 29: 506-510.    
  • 52. Eggen BJL, Raj D, Hanisch UK, et al. (2013) Microglial Phenotype and Adaptation. J Neuroimmune Pharmacol 8: 807-823.    
  • 53. Colton CA (2012) Immune Heterogeneity in Neuroinflammation: Dendritic Cells in the Brain. J Neuroimmune Pharmacol 8: 145-162.
  • 54. Breunig JJ, Guillot-Sestier M-V, Town T (2013) Brain injury, neuroinflammation and Alzheimer's disease. Front Aging Neurosci 5: 26.
  • 55. Doty KR, Guillot-Sestier M-V, Town T (2014) The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive? Brain
  • 56. Foley E, O'Farrell PH (2003) Nitric oxide contributes to induction of innate immune responses to gram-negative bacteria in Drosophila. Genes Dev 17: 115-125.    
  • 57. Novakova M, Dolezal T (2011) Expression of Drosophila Adenosine Deaminase in Immune Cells during Inflammatory Response. PLoS ONE 6: e17741.    
  • 58. Brown S, Hu N, Hombría JC-G (2001) Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr Biol 11: 1700-1705.    
  • 59. Johansson K, Metzendorf C, Soderhall K (2005) Microarray analysis of immune challenged hemocytes. Exp Cell Res 305: 145-155.    
  • 60. Inamdar AA, Bennett JW (2014) A common fungal volatile organic compound induces a nitric oxide mediated inflammatory response in Drosophila melanogaster. Sci Rep
  • 61. Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91: 461-553.    
  • 62. Wood W, Jacinto A (2007) Drosophila melanogaster embryonic haemocytes: masters of multitasking. Nat Rev Mol Cell Biol 8: 542-551.    
  • 63. Garay P, McAllister K (2010) Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders. Front Syn Neurosci. 2: 1-16.
  • 64. Kaneko M, Stellwagen D, Malenka RC, Stryker MP (2008) Tumor Necrosis Factor-α Mediates One Component of Competitive, Experience-Dependent Plasticity in Developing Visual Cortex. Neuron 58: 673-680.    
  • 65. Royet J, Reichhart J-M, Hoffmann JA (2005) Sensing and signaling during infection in Drosophila. Curr Opin Immunol 17: 11-17.    
  • 66. Copf T, Goguel V, Lampin-Saint-Amaux A, et al. (2011) Cytokine signaling through the JAK/STAT pathway is required for long-term memory in Drosophila. Proc Natl Acad Sci U S A108: 8059-8064.
  • 67. Zhang X, Zhang Y (2012) DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning. Proc Natl Acad Sci U S A 109: 17081-17086.    
  • 68. Zugasti O, Ewbank JJ (2009) Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-β signaling pathway in Caenorhabditis elegans epidermis. Nat Immunol 10:249-256.    
  • 69. Town T, Laouar Y, Pittenger C, et al. (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14: 681-687.
  • 70. Mitchell K, Shah JP, Tsytsikova LV, et al. (2014) LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia. J Neurochem 129: 155-168.    
  • 71. Bialas AR, Stevens B (2013) TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 16: 1773-1782.    
  • 72. Zhang Y, Shan B, Boyle M, et al. (2014) Brain Proteome Changes Induced by Olfactory Learning in Drosophila. J Proteome Res 13:3763–3770.
  • 73. D'Ambrosio MV, Vale RD (2010) A whole genome RNAi screen of Drosophila S2 cell spreading performed using automated computational image analysis. J Cell Biol 191: 471-478.    
  • 74. Williams DW, Truman JW (2005) Cellular mechanisms of dendrite pruning in Drosophila: insights from in vivo time-lapse of remodeling dendritic arborizing sensory neurons. Development 132: 3631-3642.    
  • 75. Lesch C, Goto A, Lindgren M, et al. (2007) A role for Hemolectin in coagulation and immunity in Drosophila melanogaster. Dev Comp Immunol 31: 1255-1263.    
  • 77. Barrangou R (2015) The roles of CRISPR–Cas systems in adaptive immunity and beyond. Curr Opin Immunol 32: 36-41.    
  • 78. Um P (2015) Immunity, Innate: Definition and Examples. In: Highlander S, Rodriguez-Valera F, White B (eds) Encyclopedia of Metagenomics. Boston: Springer US.
  • 79. Westra ER, Buckling A, Fineran PC (2014) CRISPR-Cas systems: beyond adaptive immunity. Nat Rev Micro 12: 317-326.    
  • 80. Lange C, Hemmrich G, Klostermeier UC, et al. (2011) Defining the Origins of the NOD-Like Receptor System at the Base of Animal Evolution. Mol Biol Evol 28: 1687-1702.    
  • 81. Sunyer JO (2013) Fishing for mammalian paradigms in the teleost immune system. Nat Immunol 14: 320-326.    
  • 82. Uribe C, Folch H, Enriquez R, et al. (2011) Innate and adaptive immunity in teleost fish: a review. Vet Med 56: 486-503.
  • 83. Ting JP-Y, Davis BK (2004) CATERPILLER: A Novel Gene Family Important in Immunity, Cell Death, and Diseases. Annu Rev Immunol 23: 387-414.
  • 84. Pham LN, Dionne MS, Shirasu-Hiza M, et al. (2007) A Specific Primed Immune Response in Drosophila Is Dependent on Phagocytes. PLoS Pathog 3: e26.    
  • 85. Schneider DS (2007) How and Why Does a Fly Turn Its Immune System Off? PLoS Biol 5: e247.    
  • 86. Ayres JS, Schneider DS (2012) Tolerance of Infections. Annu Rev Immunol 30: 271-294.    
  • 87. Chambers MC, Schneider DS (2012) Pioneering immunology: insect style. Curr Opin Immunol24: 10-14.
  • 88. Dong Y, Cirimotich CM, Pike A, et al. (2012) Anopheles NF-κB-Regulated Splicing Factors Direct Pathogen-Specific Repertoires of the Hypervariable Pattern Recognition Receptor AgDscam. Cell Host Microbe 12: 521-530.    
  • 89. Schmucker D, Chen B (2009) Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes. Genes Dev 23: 147-156.    
  • 90. Kounatidis I, Ligoxygakis P (2012) Drosophila as a model system to unravel the layers of innate immunity to infection. Open Biol 2: 120075.    
  • 91. Marsh EK, May RC (2012) Caenorhabditis elegans, a Model Organism for Investigating Immunity. Appl Environ Microbiol 78: 2075-2081.    
  • 92. Oikonomou G, Shaham S (2010) The Glia of Caenorhabditis elegans. Glia 59: 1253-1263.
  • 93. Kraft-Terry SD, Buch SJ, Fox HS, Gendelman HE (2009) A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron 64: 133-145.    
  • 94. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421: 499-506.    
  • 95. Derheimer FA, Kastan MB (2010) Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Letters 584: 3675-3681.    
  • 96. Yang Y, Herrup K (2005) Loss of Neuronal Cell Cycle Control in Ataxia-Telangiectasia: A Unified Disease Mechanism. J Neurosci 25: 2522-2529.    
  • 97. Pandey UB, Nichols CD (2011) Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery. Pharmacol Rev 63: 411-436.    
  • 98. Crotti A, Benner C, Kerman BE, et al. (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 17: 513-521.    
  • 99. Holtzman DM, Mandelkow E, Selkoe DJ (2012) Alzheimer Disease in 2020. Cold Spring Harb Perspect Med 2: a011585-a011585.
  • 100. Selkoe DJ (2012) Preventing Alzheimer's Disease. Science 337: 1488-1492.    
  • 101. Iijima K, Liu H-P, Chiang A-S, et al. (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease. Proc Natl Acad Sci U S A 101: 6623-6628.    
  • 102.Mhatre SD, Paddock BE, Saunders AJ, et al. (2013) Invertebrate Models of Alzheimer's Disease. J Alzheimers Dis 33: 3-16.
  • 103. Guo M, Hong EJ, Fernandes J, et al. (2003) A reporter for amyloid precursor protein γ-secretase activity in Drosophila. Hum Mol Genet 12: 2669-2678.    
  • 104. Shaw JL, Chang KT (2013) Nebula/DSCR1 Upregulation Delays Neurodegeneration and Protects against APP-Induced Axonal Transport Defects by Restoring Calcineurin and GSK-3β Signaling. PLoS Genet 9: e1003792.    
  • 105. Hickman SE, Kingery ND, Ohsumi TK, et al. (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 16: 1896-1905.    


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