A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner: microglial IL-6 regulation of experimental autoimmune encephalomyelitis.
Conditional reversible IL-6 knockout
DIO technology
Experimental autoimmune encephalomyelitis
Microglial IL-6
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
15 Oct 2020
15 Oct 2020
Historique:
received:
22
07
2020
accepted:
28
09
2020
entrez:
16
10
2020
pubmed:
17
10
2020
medline:
6
8
2021
Statut:
epublish
Résumé
Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6. To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss of Il6 expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglial Il6 expression in IL6-DIO-KO mice through breeding to Cx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10-16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglial Il6 was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology. IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.
Sections du résumé
BACKGROUND
BACKGROUND
Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6.
METHODS
METHODS
To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss of Il6 expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglial Il6 expression in IL6-DIO-KO mice through breeding to Cx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10-16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG
RESULTS
RESULTS
IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglial Il6 was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology.
CONCLUSIONS
CONCLUSIONS
IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.
Identifiants
pubmed: 33059703
doi: 10.1186/s12974-020-01969-0
pii: 10.1186/s12974-020-01969-0
pmc: PMC7565836
doi:
Substances chimiques
Interleukin-6
0
Lipopolysaccharides
0
interleukin-6, mouse
0
Cre recombinase
EC 2.7.7.-
Integrases
EC 2.7.7.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
304Subventions
Organisme : Ministerio de Economía y Competitividad
ID : SAF2014-56546-R
Organisme : Ministerio de Economía y Competitividad
ID : RTI2018-101105-B-I00
Organisme : European Regional Development Fund
ID : SAF2014-56546-R
Organisme : European Regional Development Fund
ID : RTI2018-101105-B-I00
Références
J Immunol. 2009 Aug 1;183(3):2079-88
pubmed: 19597000
Nature. 2006 May 11;441(7090):235-8
pubmed: 16648838
Immunity. 2013 Jan 24;38(1):79-91
pubmed: 23273845
Gene Ther. 2006 Oct;13(19):1382-90
pubmed: 16724096
Cytokine. 2014 Aug;68(2):86-93
pubmed: 24845797
J Immunol. 1998 Dec 15;161(12):6480-6
pubmed: 9862671
J Neurosci. 2008 Jul 9;28(28):7025-30
pubmed: 18614669
Glia. 2013 Apr;61(4):587-600
pubmed: 23322593
Science. 2010 Nov 5;330(6005):841-5
pubmed: 20966214
Cells. 2020 Jan 31;9(2):
pubmed: 32023844
J Neurosci Res. 2005 Aug 1;81(3):374-89
pubmed: 15959904
Nature. 2009 Jun 4;459(7247):663-7
pubmed: 19396156
Nature. 2009 Jun 4;459(7247):698-702
pubmed: 19396159
Science. 2000 Nov 10;290(5494):1170-4
pubmed: 11073458
J Neuroimmunol. 1991 Feb;31(2):147-53
pubmed: 1991821
Brain. 2007 Nov;130(Pt 11):2800-15
pubmed: 17956913
Nat Immunol. 2017 Jan;18(1):74-85
pubmed: 27893700
Mol Cell Neurosci. 2010 Oct;45(2):132-8
pubmed: 20600933
Nature. 2007 Feb 8;445(7128):661-5
pubmed: 17251932
Glia. 2020 May;68(5):999-1016
pubmed: 31799746
Cell. 1985 Jun;41(2):343-5
pubmed: 2985274
Science. 2009 May 22;324(5930):1080-4
pubmed: 19389999
BMC Biol. 2012 Nov 30;10:96
pubmed: 23198860
Nature. 1994 Mar 24;368(6469):339-42
pubmed: 8127368
Glia. 2002 Nov;40(2):140-55
pubmed: 12379902
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9041-6
pubmed: 18577591
Immunity. 2003 Jul;19(1):71-82
pubmed: 12871640
Eur J Immunol. 1998 May;28(5):1727-37
pubmed: 9603480
Brain Behav Immun. 2013 Jan;27(1):162-73
pubmed: 23085146
Genesis. 2000 Nov-Dec;28(3-4):106-10
pubmed: 11105051
Brain Sci. 2016 May 17;6(2):
pubmed: 27196935
Eur J Immunol. 1998 Jul;28(7):2178-87
pubmed: 9692887
Int Immunol. 1998 May;10(5):703-8
pubmed: 9645618
Genesis. 2006 Mar;44(3):115-21
pubmed: 16496309
Science. 2017 Jun 23;356(6344):
pubmed: 28546318
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6991-5
pubmed: 7624356
J Exp Med. 2013 Dec 16;210(13):2921-37
pubmed: 24323356
Nat Neurosci. 2011 Jul 31;14(9):1142-9
pubmed: 21804537
Nat Neurosci. 2007 Dec;10(12):1538-43
pubmed: 18026097
J Neurol Sci. 1997 Feb 27;146(1):59-65
pubmed: 9077497
J Mol Biol. 1981 Aug 25;150(4):467-86
pubmed: 6276557
Nat Rev Cancer. 2010 Jul;10(7):470-80
pubmed: 20574449
Int J Biol Sci. 2012;8(9):1254-66
pubmed: 23136554
Science. 2007 Feb 23;315(5815):1143-7
pubmed: 17289941
Nature. 2007 Jul 26;448(7152):484-487
pubmed: 17581588
Glia. 2009 May;57(7):777-90
pubmed: 19031437
Front Cell Neurosci. 2016 Oct 20;10:243
pubmed: 27812322
Anal Quant Cytol Histol. 2001 Aug;23(4):291-9
pubmed: 11531144
Nat Neurosci. 2013 Nov;16(11):1618-26
pubmed: 24077561
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13939-44
pubmed: 19666516
Mol Cell Biol. 2000 Jun;20(11):4106-14
pubmed: 10805752
FASEB J. 2011 Dec;25(12):4088-107
pubmed: 21891781
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Brain Behav Immun. 2010 May;24(4):641-51
pubmed: 20138983