title: DNA sensors are expressed in astrocytes and microglia in vitro and are upregulated during gliosis in neurodegenerative disease.
abstract: The detection of nucleic acids by the innate immune system is an essential host response during viral infection. In recent years, a number of immune sensors capable of recognizing cytosolic DNA have been identified and include the PYHIN family members AIM2, IFI16, and p204 as well as the enzyme, cGAS. Activation of these receptors leads to the induction of antiviral genes including Type-1 interferons and chemokines such as CCL5. We have carried out extensive expression profiling of these DNA sensors and other members of the PYHIN family in highly purified primary astrocytes and microglia and have demonstrated that both cell types express the majority of these proteins at the mRNA level. In microglia, several family members are highly upregulated in response to IFN-β treatment while both cell types induce robust proinflammatory and antiviral cytokine production (e.g., IL-6, CCL5, IFN-β) in the presence of immune stimulatory DNA and RNA. The production of IL-6 is partially dependent on the interferon receptor as is IFN-β itself. Furthermore, we have found that p204 and AIM2 are upregulated in a Type I IFN dependent fashion in vivo, in a murine model of chronic neurodegeneration. Given the propensity of inflammatory responses to cause neuronal damage, increased expression and activation of these receptors, not only during viral infection but also during sterile inflammatory responses, has the potential to exacerbate existing neuroinflammation leading to further damage and impaired neurogenesis.
authors: Molecular Immunology Group, School, of Biochemistry and Immunology and Immunology Research Centre, Trinity College Dublin, Ireland.
authors: Donal J
authors: DJ
authors: Cox
authors: Robert H
authors: RH
authors: Field
authors: David G
authors: DG
authors: Williams
authors: Marcin
authors: M
authors: Baran
authors: Andrew G
authors: AG
authors: Bowie
authors: Colm
authors: C
authors: Cunningham
authors: Aisling
authors: A
authors: Dunne
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000150:complications*; D009687:Nuclear Proteins / Q000378:metabolism*; D009696:Nucleic Acids / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; C489664:Ifi16 protein, mouse; D009687:Nuclear Proteins; D009696:Nucleic Acids; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D053633:Receptor, Interferon alpha-beta
keywords: Type I interferon; astrocytes; microglia; neurodegeneration; nucleic acid sensing
references: Hippocampus. 2013 Aug;23(8):696-707
references: 23554175
references: Immunobiology. 2013 Nov;218(11):1312-21
references: 23962476
references: Science. 2013 Sep 20;341(6152):1390-4
references: 23989956
references: Nature. 2014 Jan 30;505(7485):691-5
references: 24284630
references: Trends Immunol. 2014 Feb;35(2):79-87
references: 24316012
references: J Biol Chem. 2014 Feb 14;289(7):4532-45
references: 24366862
references: J Cereb Blood Flow Metab. 2014 Mar;34(3):369-75
references: 24398940
references: Nat Immunol. 2014 Apr;15(4):343-53
references: 24531343
references: J Cereb Blood Flow Metab. 2014 Apr;34(4):621-9
references: 24398937
references: Nat Rev Immunol. 2014 Jul;14(7):463-77
references: 24962261
references: Glia. 2014 Sep;62(9):1418-34
references: 24807365
references: J Virol. 2003 Apr;77(7):4004-14
references: 12634360
references: Neurobiol Dis. 2005 Mar;18(2):258-69
references: 15686954
references: Acta Neurochir Suppl. 2005;95:471-4
references: 16463903
references: Brain Behav Immun. 2007 May;21(4):490-502
references: 17321719
references: J Neuroinflammation. 2007;4:26
references: 17937799
references: Stroke. 2008 Sep;39(9):2560-70
references: 18635850
references: Biol Psychiatry. 2009 Feb 15;65(4):304-12
references: 18801476
references: Nat Immunol. 2009 Mar;10(3):266-72
references: 19158679
references: Science. 2009 Feb 20;323(5917):1057-60
references: 19131592
references: Nature. 2009 Mar 26;458(7237):514-8
references: 19158675
references: Nature. 2009 Mar 26;458(7237):509-13
references: 19158676
references: FASEB J. 2009 Apr;23(4):1064-71
references: 19036857
references: J Neurol. 2009 May;256(5):796-802
references: 19252806
references: Cell. 2009 Aug 7;138(3):576-91
references: 19631370
references: Neurology. 2009 Sep 8;73(10):768-74
references: 19738171
references: Nat Immunol. 2009 Oct;10(10):1065-72
references: 19609254
references: PLoS Pathog. 2009 Nov;5(11):e1000648
references: 19893623
references: J Neurovirol. 2008 Nov;14(6):503-13
references: 18991139
references: Brain Behav Immun. 2010 Aug;24(6):996-1007
references: 20399848
references: J Immunol. 2010 Jul 15;185(2):1258-64
references: 20562259
references: J Neurosci. 2010 Jul 28;30(30):10086-95
references: 20668193
references: Glia. 2010 Oct;58(13):1620-9
references: 20578054
references: Neurosci Lett. 2010 Sep 20;482(1):17-20
references: 20599470
references: Nat Immunol. 2010 Nov;11(11):997-1004
references: 20890285
references: Lancet Infect Dis. 2010 Dec;10(12):835-44
references: 20952256
references: Clin Chim Acta. 2011 Feb 20;412(5-6):476-9
references: 21130757
references: Glia. 2011 Jun;59(6):946-58
references: 21446050
references: Cell Host Microbe. 2011 May 19;9(5):363-75
references: 21575908
references: Immunol Rev. 2011 Sep;243(1):109-18
references: 21884171
references: Trends Immunol. 2011 Dec;32(12):574-81
references: 21940216
references: Glia. 2012 Mar;60(3):414-21
references: 22161971
references: Glia. 2012 Apr;60(4):630-8
references: 22271465
references: BMC Evol Biol. 2012;12:140
references: 22871040
references: Science. 2013 Feb 15;339(6121):826-30
references: 23258412
references: Science. 2013 Feb 15;339(6121):786-91
references: 23258413
references: J Immunol. 2013 Mar 15;190(6):2807-17
references: 23382563
references: Virol J. 2013;10:172
references: 23724961
references: Epilepsy Res. 2013 Aug;105(3):292-8
references: 23582956