title: Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis.
abstract: Microglia are the resident brain macrophages and they have been traditionally studied as orchestrators of the brain inflammatory response during infections and disease. In addition, microglia has a more benign, less explored role as the brain professional phagocytes. Phagocytosis is a term coined from the Greek to describe the receptor-mediated engulfment and degradation of dead cells and microbes. In addition, microglia phagocytoses brain-specific cargo, such as axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-β deposits in Alzheimer's disease, and supernumerary synapses in postnatal development. Common mechanisms of recognition, engulfment, and degradation of the different types of cargo are assumed, but very little is known about the shared and specific molecules involved in the phagocytosis of each target by microglia. More importantly, the functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon, since it eliminates dead cells and induces an anti-inflammatory response. However, phagocytosis can also activate the respiratory burst, which produces toxic reactive oxygen species (ROS). Phagocytosis has been traditionally studied in pathological conditions, leading to the assumption that microglia have to be activated in order to become efficient phagocytes. Recent data, however, has shown that unchallenged microglia phagocytose apoptotic cells during development and in adult neurogenic niches, suggesting an overlooked role in brain remodeling throughout the normal lifespan. The present review will summarize the current state of the literature regarding the role of microglial phagocytosis in maintaining tissue homeostasis in health as in disease.
authors: Achucarro-Basque Center for Neuroscience Zamudio, Spain ; Department of Neuroscience, University of the Basque Country EHU/UPV Leioa, Spain ; Ikerbasque-Basque Foundation for Science Bilbao, Spain.
authors: Amanda
authors: A
authors: Sierra
authors: Oihane
authors: O
authors: Abiega
authors: Anahita
authors: A
authors: Shahraz
authors: Harald
authors: H
authors: Neumann
keywords: amyloid; apoptosis; debris; inflammation; microglia; myelin; phagocytosis; synapses
references: Blood. 2008 Dec 15;112(13):5026-36
references: 18799722
references: J Neurosci. 2011 Sep 7;31(36):12992-3001
references: 21900578
references: J Neurosci Res. 2008 May 15;86(7):1434-47
references: 18061944
references: Biochem Soc Trans. 2011 Aug;39(4):886-90
references: 21787318
references: Physiology (Bethesda). 2010 Feb;25(1):8-15
references: 20134024
references: Glia. 1993 Nov;9(3):199-210
references: 7507467
references: Trends Biochem Sci. 2012 Aug;37(8):325-32
references: 22682109
references: Ann Neurol. 2011 Jan;69(1):170-80
references: 21280087
references: J Neurochem. 2010 Feb;112(3):733-43
references: 19919576
references: Free Radic Biol Med. 2010 Dec 15;49(12):1834-45
references: 20870019
references: Cell. 2008 May 30;133(5):916-27
references: 18510934
references: J Cell Biol. 1994 Mar;124(5):677-88
references: 8120091
references: Cell. 2001 Oct 5;107(1):27-41
references: 11595183
references: J Neurosci. 2000 Nov 15;20(22):8435-42
references: 11069951
references: Front Biosci. 2008 Jan 01;13:62-70
references: 17981528
references: J Neuroimmunol. 2010 Oct 8;227(1-2):111-9
references: 20655116
references: Neuro Oncol. 2010 Nov;12(11):1113-25
references: 20667896
references: Mucosal Immunol. 2008 May;1(3):229-38
references: 19079182
references: Front Neuroenergetics. 2010 Oct 12;2:131
references: 21031160
references: J Clin Invest. 1998 Feb 15;101(4):890-8
references: 9466984
references: Proteomics. 2010 Nov;10(22):4098-116
references: 21080496
references: Microbiology (Reading). 2011 Jun;157(Pt 6):1816-1822
references: 21474536
references: J Cell Biol. 2001 Nov 12;155(4):649-59
references: 11706053
references: J Biol Chem. 1999 Nov 5;274(45):32301-8
references: 10542270
references: Science. 2011 Sep 9;333(6048):1456-8
references: 21778362
references: Front Neuroendocrinol. 2012 Jan;33(1):116-25
references: 22214786
references: Biomed Pharmacother. 1999 Apr;53(3):146-8
references: 10349503
references: J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21
references: 12430718
references: J Exp Med. 2005 Feb 21;201(4):647-57
references: 15728241
references: J Neurosci. 2005 Sep 7;25(36):8240-9
references: 16148231
references: J Immunol. 1995 May 1;154(9):4309-21
references: 7722289
references: Cancer Res. 2007 Oct 1;67(19):9398-406
references: 17909049
references: J Neurosci. 2010 Dec 15;30(50):17091-101
references: 21159979
references: J Neuroimmune Pharmacol. 2009 Jun;4(2):200-12
references: 19016329
references: Ann N Y Acad Sci. 2001 Dec;947:214-22; discussion 222-3
references: 11795269
references: Development. 1997 Sep;124(18):3633-8
references: 9342055
references: Cell Cycle. 2007 Mar 15;6(6):686-95
references: 17361099
references: Glia. 2005 Mar;49(4):567-76
references: 15593098
references: Glia. 2010 Dec;58(16):2017-30
references: 20878768
references: J Biol Chem. 2009 Aug 7;284(32):21626-36
references: 19531468
references: Cell. 1993 Aug 13;74(3):453-62
references: 8348612
references: Brain. 2005 Aug;128(Pt 8):1778-89
references: 15857927
references: J Lipid Res. 2011 Aug;52(8):1542-50
references: 21572087
references: J Immunol. 2004 Feb 1;172(3):1882-7
references: 14734773
references: Int J Alzheimers Dis. 2012;2012:983640
references: 22957298
references: J Immunol. 1993 Jul 1;151(1):330-8
references: 8326130
references: Int J Hematol. 2006 Oct;84(3):193-8
references: 17050190
references: J Biol Chem. 2004 Jan 9;279(2):1415-21
references: 14578353
references: J Immunol. 2012 Feb 1;188(3):1098-107
references: 22198949
references: Future Neurol. 2012 Mar 1;7(2):165-176
references: 22737039
references: J Neurosci. 2005 Jun 1;25(22):5333-8
references: 15930381
references: Nat Immunol. 2003 Feb;4(2):138-44
references: 12524536
references: Glia. 2001 Jan;33(1):87-95
references: 11169794
references: Cell. 2011 Dec 23;147(7):1442-5
references: 22196723
references: Glia. 2012 Feb;60(2):306-21
references: 22072381
references: J Neurosci. 2012 Feb 22;32(8):2657-66
references: 22357850
references: Annu Rev Immunol. 2009;27:119-45
references: 19302036
references: Nature. 2008 Feb 7;451(7179):720-4
references: 18256671
references: Am J Pathol. 2006 Jul;169(1):154-64
references: 16816369
references: Cell Mol Life Sci. 2011 May;68(9):1581-92
references: 20953657
references: Science. 2012 Apr 6;336(6077):86-90
references: 22442384
references: EMBO Rep. 2011 Apr;12(4):287-8
references: 21399618
references: J Neurochem. 2009 Jul;110(1):284-94
references: 19457124
references: J Immunol. 2004 Oct 1;173(7):4582-9
references: 15383592
references: Exp Neurol. 2004 Nov;190(1):245-53
references: 15473997
references: J Neurosci. 2008 Aug 6;28(32):8138-43
references: 18685038
references: Neurobiol Dis. 2007 Apr;26(1):47-55
references: 17270453
references: Blood. 2003 Oct 15;102(8):2940-7
references: 12842997
references: J Neuropathol Exp Neurol. 2002 Mar;61(3):237-44
references: 11895038
references: J Neuroinflammation. 2008 Oct 09;5:43
references: 18844999
references: Genes Dev. 2000 Mar 1;14(5):549-58
references: 10716943
references: Am J Pathol. 2009 Dec;175(6):2528-39
references: 19893026
references: Nat Med. 2005 Feb;11(2):146-52
references: 15665833
references: Nature. 2001 Jul 12;412(6843):198-202
references: 11449278
references: Int J Alzheimers Dis. 2012;2012:737846
references: 22655214
references: Annu Rev Neurosci. 2005;28:127-56
references: 16022592
references: Neuro Oncol. 2006 Jul;8(3):261-79
references: 16775224
references: Nat Med. 1997 Jan;3(1):73-6
references: 8986744
references: Neurochem Int. 2012 Dec;61(7):1021-35
references: 22847064
references: J Neurosci. 2008 Nov 12;28(46):12023-12031
references: 19005067
references: J Neurosci. 2012 Jan 18;32(3):946-52
references: 22262892
references: J Comp Neurol. 2003 Mar 31;458(2):144-57
references: 12596255
references: J Immunol. 2001 Nov 1;167(9):5004-10
references: 11673508
references: J Pediatr Surg. 2007 Jun;42(6):927-32; discussion 933
references: 17560196
references: Microsc Res Tech. 2002 Jun 15;57(6):541-7
references: 12112437
references: J Neurosci. 2009 Apr 1;29(13):3974-80
references: 19339593
references: Glia. 2004 Apr 15;46(2):101-15
references: 15042579
references: Prog Neurobiol. 1999 Apr;57(6):563-81
references: 10221782
references: Nat Neurosci. 2009 Dec;12(12):1534-41
references: 19915564
references: Acta Physiol (Oxf). 2010 Jan;198(1):15-35
references: 19732041
references: Curr Top Microbiol Immunol. 2009;336:137-53
references: 19688332
references: Am J Pathol. 2010 Nov;177(5):2549-62
references: 20864679
references: Neuropathology. 2011 Aug;31(4):363-75
references: 21118401
references: J Immunol. 2008 Mar 1;180(5):2777-85
references: 18292498
references: J Neurosci Res. 2005 Aug 1;81(3):447-55
references: 15959903
references: Nat Rev Neurosci. 2007 Jan;8(1):57-69
references: 17180163
references: PLoS Med. 2007 Apr;4(4):e124
references: 17425404
references: Exp Neurol. 1993 May;121(1):113-8
references: 8495706
references: J Biol Chem. 2004 Jul 9;279(28):29450-60
references: 15123631
references: Glia. 2010 May;58(7):823-30
references: 20091776
references: J Neurosci. 2008 Aug 13;28(33):8354-60
references: 18701698
references: Exp Physiol. 2005 Sep;90(5):663-70
references: 15944202
references: J Cereb Blood Flow Metab. 2012 Sep;32(9):1677-98
references: 22739623
references: Science. 2010 Nov 5;330(6005):841-5
references: 20966214
references: Neuron. 2007 Mar 1;53(5):649-62
references: 17329206
references: J Neuroinflammation. 2011 Jul 25;8:85
references: 21781347
references: Trends Immunol. 2006 May;27(5):244-50
references: 16584921
references: Glia. 2009 Feb;57(3):320-35
references: 18756527
references: Neuron. 2004 Feb 19;41(4):535-47
references: 14980203
references: J Immunol. 2009 Feb 15;182(4):1982-90
references: 19201851
references: Brain Res Brain Res Rev. 1999 Jul;30(1):77-105
references: 10407127
references: Cell Mol Neurobiol. 2004 Feb;24(1):1-24
references: 15049507
references: J Immunol. 2009 Nov 15;183(10):6452-9
references: 19864601
references: Nature. 2002 Jun 27;417(6892):941-4
references: 12068310
references: Curr Biol. 2000 Jul 13;10(14):857-60
references: 10899007
references: Am J Hum Genet. 2002 Sep;71(3):656-62
references: 12080485
references: Annu Rev Pathol. 2012;7:61-98
references: 21910624
references: Glia. 2012 May;60(5):717-27
references: 22290798
references: Cell. 2010 Mar 5;140(5):619-30
references: 20211132
references: Nat Rev Neurosci. 2012 Jun 20;13(7):507-14
references: 22714021
references: Glia. 2003 Apr 1;42(1):89-100
references: 12594740
references: Nat Rev Immunol. 2012 Jun 15;12(7):492-502
references: 22699831
references: J Neuroinflammation. 2011 Aug 30;8:110
references: 21878126
references: J Neurosci. 2008 Jun 4;28(23):5965-75
references: 18524901
references: J Neurosci. 2010 Mar 3;30(9):3482-8
references: 20203208
references: Immunology. 1994 Sep;83(1):140-7
references: 7821959
references: Brain. 2004 Jan;127(Pt 1):34-44
references: 14534158
references: Am J Pathol. 1996 Sep;149(3):911-21
references: 8780395
references: J Neurochem. 2007 Jun;101(5):1205-13
references: 17403030
references: J Immunol. 2000 Jun 15;164(12):6520-9
references: 10843710
references: Trends Immunol. 2002 Nov;23(11):549-55
references: 12401408
references: Nat Rev Mol Cell Biol. 2001 Aug;2(8):589-98
references: 11483992
references: Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4441-6
references: 21368173
references: Nat Rev Immunol. 2002 Dec;2(12):965-75
references: 12461569
references: J Neuroimmune Pharmacol. 2008 Jun;3(2):130-40
references: 18247125
references: J Exp Med. 2006 Nov 27;203(12):2613-25
references: 17101731
references: Nat Rev Immunol. 2005 Nov;5(11):866-79
references: 16261174
references: Mol Cell. 2004 May 7;14(3):277-87
references: 15125832
references: Immunol Rev. 2011 May;241(1):228-40
references: 21488900
references: J Exp Med. 2012 Jun 4;209(6):1167-81
references: 22565823
references: Neuron. 1996 Sep;17(3):553-65
references: 8816718
references: Biochemistry. 2005 Jun 21;44(24):8841-9
references: 15952790
references: Cell Signal. 2012 Jul;24(7):1420-5
references: 22446004
references: Cell. 1992 Jul 10;70(1):31-46
references: 1623522
references: J Neuroimmunol. 2011 Mar;232(1-2):75-82
references: 21056915
references: Microsc Res Tech. 2001 Jul 15;54(2):81-94
references: 11455615
references: J Neuroinflammation. 2011 Nov 10;8:157
references: 22074485
references: Neuron. 2006 Feb 16;49(4):489-502
references: 16476660
references: Mol Biol Cell. 2007 Aug;18(8):2883-92
references: 17507658
references: Ann Neurol. 2005 Jan;57(1):67-81
references: 15546155
references: J Neurosci Res. 1999 Nov 1;58(3):387-95
references: 10518112
references: J Immunol. 1999 Jan 15;162(2):939-47
references: 9916718
references: Nature. 2007 Apr 26;446(7139):1091-5
references: 17410128
references: Cold Spring Harb Perspect Biol. 2011 Mar 01;3(3):
references: 21068150
references: J Neuropathol Exp Neurol. 2009 Aug;68(8):845-56
references: 19606068
references: J Neurosci. 2006 Dec 13;26(50):12904-13
references: 17167081
references: Nat Cell Biol. 2011 Jul 31;13(9):1076-83
references: 21804544
references: EMBO Rep. 2011 Apr;12(4):358-64
references: 21399623
references: J Mol Neurosci. 2009 Sep;39(1-2):99-103
references: 19253007
references: J Clin Invest. 2003 Feb;111(3):323-32
references: 12569157
references: Infect Immun. 2010 Feb;78(2):865-71
references: 19933834
references: Channels (Austin). 2007 Sep-Oct;1(5):366-76
references: 18690036
references: Nature. 2009 Sep 10;461(7261):282-6
references: 19741708
references: Neurosci Lett. 2007 Apr 6;416(1):87-91
references: 17317005
references: J Comp Neurol. 2008 Jun 10;508(5):687-710
references: 18386786
references: Glia. 2008 Aug 15;56(11):1215-23
references: 18449945
references: Eur J Neurosci. 2001 Aug;14(3):474-82
references: 11553297
references: J Neurosci. 2004 Dec 15;24(50):11421-8
references: 15601948
references: Mol Cell Biol. 2012 Jul;32(14):2698-708
references: 22566688
references: Immunol Rev. 2010 May;235(1):172-89
references: 20536563
references: J Immunol. 2011 Apr 15;186(8):4973-83
references: 21402900
references: Nature. 2012 Mar 18;484(7392):105-9
references: 22425995
references: J Leukoc Biol. 1994 Dec;56(6):732-40
references: 7996050
references: J Leukoc Biol. 2004 Oct;76(4):760-81
references: 15240752
references: Genes Dev. 2001 Jun 1;15(11):1311-33
references: 11390353
references: Neurobiol Aging. 2001 May-Jun;22(3):427-34
references: 11378249
references: Nat Immunol. 2006 Dec;7(12):1266-73
references: 17110943
references: J Cell Biol. 2001 Jan 8;152(1):165-80
references: 11149929
references: Genes Dev. 1994 Feb 15;8(4):387-98
references: 8125254
references: Brain Res Dev Brain Res. 1996 Nov 22;97(1):1-8
references: 8946048
references: Trends Immunol. 2007 Jan;28(1):12-8
references: 17129764
references: Cell Stem Cell. 2010 Oct 8;7(4):483-95
references: 20887954
references: Cell Death Differ. 2003 Oct;10(10):1156-64
references: 14502239
references: Pathol Oncol Res. 2012 Oct;18(4):771-81
references: 22714538
references: Nat Neurosci. 2005 Jun;8(6):752-8
references: 15895084
references: Infect Immun. 2012 Jun;80(6):2076-88
references: 22431652
references: Glia. 2013 Jan;61(1):37-46
references: 22615186
references: PLoS Biol. 2010 Nov 02;8(11):e1000527
references: 21072242
references: J Exp Med. 2001 Sep 17;194(6):781-95
references: 11560994
references: Mol Med. 1997 Nov;3(11):750-64
references: 9407551
references: Cell Mol Life Sci. 2005 Oct;62(19-20):2173-93
references: 16132232
references: J Neuroinflammation. 2011 Mar 15;8:24
references: 21401967
references: J Neuroimmunol. 2004 Aug;153(1-2):76-82
references: 15265665
references: J Immunol. 2003 Jul 15;171(2):594-9
references: 12847223
references: Acta Neuropathol. 2004 Mar;107(3):204-8
references: 14689205
references: J Biol Chem. 2011 Jan 21;286(3):2308-19
references: 21071446
references: Physiol Rev. 1997 Jul;77(3):759-803
references: 9234965
references: J Clin Invest. 2012 Apr;122(4):1149-55
references: 22466656
references: Small GTPases. 2011 Sep;2(5):268-275
references: 22292130
references: J Neuroinflammation. 2010 Apr 29;7:28
references: 20429874
references: Nature. 1997 Nov 27;390(6658):350-1
references: 9389474
references: Nat Rev Immunol. 2012 Sep;12(9):623-35
references: 22903150
references: Annu Rev Immunol. 2005;23:901-44
references: 15771589
references: Glia. 2009 Jun;57(8):835-49
references: 19053043
references: J Biol Chem. 2011 Feb 4;286(5):3693-706
references: 20971854
references: J Immunol. 2006 Sep 15;177(6):4047-54
references: 16951368
references: Glia. 2006 Jan 1;53(1):103-13
references: 16206158
references: Nature. 2007 Apr 26;446(7139):987-9
references: 17410127
references: Nat Neurosci. 2006 Oct;9(10):1234-6
references: 16980964
references: Cereb Cortex. 2012 Jun;22(6):1333-42
references: 21856714
references: J Neurochem. 2009 May;109(4):1144-56
references: 19302484
references: J Neurosci. 2012 May 30;32(22):7745-57
references: 22649252
references: J Mol Neurosci. 2003;21(1):65-72
references: 14500997
references: Brain Res Dev Brain Res. 1990 Sep 1;55(2):219-30
references: 2253324
references: Apoptosis. 2007 May;12(5):993-1010
references: 17453164
references: J Neurosci. 2011 Mar 16;31(11):4124-36
references: 21411653
references: Nature. 2002 Jul 11;418(6894):191-5
references: 12110890
references: J Immunol. 2010 Nov 15;185(10):6317-28
references: 20962261
references: J Biol Chem. 2011 Nov 18;286(46):39904-13
references: 21903584
references: J Neuropathol Exp Neurol. 2003 Feb;62(2):208-16
references: 12578230
references: Int J Alzheimers Dis. 2012;2012:891087
references: 22666624
references: Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20918-23
references: 19906988
references: J Neuroimmune Pharmacol. 2012 Jun;7(2):412-23
references: 21826404
references: J Neuropathol Exp Neurol. 2002 Sep;61(9):760-6
references: 12230322
references: Neuro Oncol. 2000 Jul;2(3):174-83
references: 11302338
references: J Cell Sci. 2008 Jun 1;121(11):1773-83
references: 18492791
references: Science. 2005 May 27;308(5726):1314-8
references: 15831717
references: Apoptosis. 2000 Feb;5(1):9-16
references: 11227497
references: Neuron. 2012 May 24;74(4):691-705
references: 22632727
references: J Cereb Blood Flow Metab. 1998 Jun;18(6):670-4
references: 9626191
references: Nat Neurosci. 2010 Apr;13(4):411-3
references: 20305648
references: Cancer Metastasis Rev. 2010 Dec;29(4):695-707
references: 20839033
references: Int J Alzheimers Dis. 2012;2012:489456
references: 22666621
references: Cancer Res. 2007 Sep 15;67(18):8874-81
references: 17875729
references: Neurosci Res. 1998 Oct;32(2):137-48
references: 9858021
references: Development. 2005 Aug;132(16):3631-42
references: 16033801
references: J Neurosci Res. 1994 Jul 1;38(4):433-43
references: 7932874
references: J Exp Med. 2010 Aug 30;207(9):1807-17
references: 20805564
references: J Neurosci. 2006 Jun 14;26(24):6413-21
references: 16775128