Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation.
Aquaporin-4 (AQP4) deficiency in mice reduces neuroinflammation in experimental autoimmune encephalomyelitis (EAE) produced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG). Potential mechanisms for the protective effect of AQP4 deficiency were investigated, including AQP4-dependent leukocyte and microglia cell function, immune cell entry in the central nervous system (CNS), intrinsic neuroinflammation, and humoral immune response. As we found with active-immunization EAE, neuroinflammation was greatly reduced in AQP4-knockout mice in adoptive-transfer EAE. AQP4 was absent in immune cells, including activated T lymphocytes. The CNS migration of fluorescently labeled, MOG-sensitized T lymphocytes was comparable in wild-type and AQP4-knockout mice. Microglia did not express AQP4. Serum anti-AQP4 antibodies were absent in EAE. Remarkably, intracerebral injection of LPS produced much greater neuroinflammation in wild-type than in AQP4-knockout mice, and cytokine (TNF-α and IL-6) secretion was reduced in astrocyte cultures from AQP4-knockout mice. Adenovirus-mediated expression of AQP4, or of an unrelated aquaporin, AQP1, increased cytokine secretion in astrocyte and nonastrocyte cell cultures, supporting the involvement of aquaporin water permeability in cytokine secretion. Our data suggest an intrinsic proinflammatory role of AQP4 involving AQP4-dependent astrocyte swelling and cytokine release. Reduction in AQP4 water transport may be protective in neuroinflammatory CNS diseases.
Department of Medicine, University of California, San Francisco, California 94143-0521, USA.
Lihua
L
Li
Hua
H
Zhang
Michel
M
Varrin-Doyer
Scott S
SS
Zamvil
A S
AS
Verkman
D000256:Adenoviridae; D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4
Brain. 2008 Apr;131(Pt 4):1087-98
18267965
J Neurochem. 2004 Nov;91(4):891-9
15525343
Ann Neurol. 2009 Nov;66(5):617-29
19938104
Brain. 2010 Feb;133(Pt 2):349-61
20047900
Curr Protoc Immunol. 2010 Feb;Chapter 15:Unit 15.1
20143314
J Cell Sci. 2005 Dec 15;118(Pt 24):5691-8
16303850
J Biol Chem. 2001 Aug 17;276(33):31233-7
11406631
J Exp Med. 2008 Jul 7;205(7):1535-41
18573909
Nat Med. 2000 Feb;6(2):159-63
10655103
Annu Rev Immunol. 2009;27:485-517
19132915
FASEB J. 2007 Jan;21(1):108-16
17135365
J Cereb Blood Flow Metab. 2006 Dec;26(12):1527-37
16552421
FASEB J. 2008 Sep;22(9):3216-23
18511552
Eur J Immunol. 2002 Jul;32(7):1905-13
12115610
J Clin Invest. 1997 Sep 1;100(5):957-62
9276712
Ann Neurol. 2010 Sep;68(3):369-83
20641064
J Clin Invest. 2006 Sep;116(9):2313-6
16955130
J Membr Biol. 2006 Mar;210(2):155-9
16868671
Ann Neurol. 2010 Jun;67(6):794-801
20517941
Dis Markers. 2006;22(4):197-206
17124341
Front Biosci. 2007 Jan 01;12:2735-49
17127276
Biophys J. 2010 Aug 9;99(4):1284-91
20713014
Brain. 2007 May;130(Pt 5):1194-205
17282996
J Biol Chem. 2005 Apr 8;280(14):13906-12
15695511
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4720-4
11917120
Biochem Biophys Res Commun. 2009 Sep 4;386(4):623-7
19545538
J Neurosci. 2008 May 21;28(21):5460-4
18495879
Brain. 2007 May;130(Pt 5):1224-34
17405762
BMC Neurosci. 2009 Aug 06;10:94
19660138
Invest Ophthalmol Vis Sci. 2002 Feb;43(2):573-9
11818406
J Exp Med. 2005 Aug 15;202(4):473-7
16087714
Am J Physiol Cell Physiol. 2004 Feb;286(2):C426-32
14576087
Glia. 2006 Apr 15;53(6):631-6
16470808
Nat Methods. 2005 Nov;2(11):825-7
16278651
Nature. 2009 Nov 5;462(7269):94-8
19829296
J Neurosci. 1997 Feb 1;17(3):932-40
8994048
Neuroscience. 2009 Jul 7;161(3):764-72
19345723
FASEB J. 2004 Aug;18(11):1291-3
15208268
Biochim Biophys Acta. 2006 Aug;1758(8):1085-93
16564496