title: Loss of astrocytic leptin signaling worsens experimental autoimmune encephalomyelitis.
abstract: Leptin is commonly thought to play a detrimental role in exacerbating experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Paradoxically, we show here that astrocytic leptin signaling has beneficial effects in reducing disease severity. In the astrocyte specific leptin receptor knockout (ALKO) mouse in which leptin signaling is absent in astrocytes, there were higher EAE scores (more locomotor deficits) than in the wildtype counterparts. The difference mainly occurred at a late stage of EAE when wildtype mice showed signs of recovery whereas ALKO mice continued to deteriorate. The more severe symptoms in ALKO mice coincided with more infiltrating cells in the spinal cord and perivascular brain parenchyma, more demyelination, more infiltrating CD4 cells, and a lower percent of neutrophils in the spinal cord 28 days after EAE induction. Cultured astrocytes from wildtype mice showed increased adenosine release in response to interleukin-6 and the hippocampus of wildtype mice had increased adenosine production 28 days after EAE induction, but the ALKO mutation abolished the increase in both conditions. This indicates a role of astrocytic leptin in normal gliotransmitter release and astrocyte functions. The worsening of EAE in the ALKO mice in the late stage suggests that astrocytic leptin signaling helps to clear infiltrating leukocytes and reduce autoimmune destruction of the CNS.
authors.affiliation: Blood-Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, United States.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mishra
authors.forename: Hung
authors.initials: H
authors.lastname: Hsuchou
authors.forename: Suidong
authors.initials: S
authors.lastname: Ouyang
authors.forename: Abba J
authors.initials: AJ
authors.lastname: Kastin
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
authors.forename: Weihong
authors.initials: W
authors.lastname: Pan
mesh_terms: D000241:Adenosine / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology
chemical_list: D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D000241:Adenosine
keywords: Adenosine; Autoimmunity; EAE; Leptin receptor; Neuroinflammation; Reactive astrogliosis
references.citation: Peptides. 2006 Jun;27(6):1420-5
references.pmid: 16293343
references.citation: J Neuroimmunol. 2007 Dec;192(1-2):174-83
references.pmid: 17904647
references.citation: Magn Reson Imaging. 1994;12(3):469-75
references.pmid: 8007777
references.citation: Peptides. 1996;17(2):305-11
references.pmid: 8801538
references.citation: J Neuroimmunol. 2010 Jun;223(1-2):65-72
references.pmid: 20430449
references.citation: J Neurosci. 2012 May 2;32(18):6391-410
references.pmid: 22553043
references.citation: Mamm Genome. 2004 Sep;15(9):677-85
references.pmid: 15389315
references.citation: J Immunol. 2011 Jun 1;186(11):6521-31
references.pmid: 21515788
references.citation: Trends Neurosci. 1997 Dec;20(12):570-7
references.pmid: 9416670
references.citation: J Mol Neurosci. 2013 Oct;51(2):364-70
references.pmid: 23504255
references.citation: J Immunol. 2012 Nov 1;189(9):4295-304
references.pmid: 23034169
references.citation: J Neuroimmunol. 2003 Jun;139(1-2):150-4
references.pmid: 12799033
references.citation: J Clin Invest. 2008 Jan;118(1):272-80
references.pmid: 18097472
references.citation: PLoS One. 2012;7(7):e42088
references.pmid: 22848713
references.citation: Biochem Biophys Res Commun. 2008 Apr 4;368(2):181-5
references.pmid: 18222172
references.citation: J Vis Exp. 2011 Feb 02;(48):
references.pmid: 21339713
references.citation: J Immunol. 2013 Jan 1;190(1):138-46
references.pmid: 23225885
references.citation: J Mol Med (Berl). 2004 Jun;82(6):364-72
references.pmid: 15007511
references.citation: J Clin Invest. 2006 Feb;116(2):447-55
references.pmid: 16410832
references.citation: J Clin Invest. 2003 Jan;111(2):241-50
references.pmid: 12531880
references.citation: Am J Physiol Endocrinol Metab. 2005 Sep;289(3):E403-11
references.pmid: 15870101
references.citation: J Immunol. 2005 Apr 15;174(8):5124-31
references.pmid: 15814744
references.citation: J Mol Neurosci. 2011 Mar;43(3):478-84
references.pmid: 21086065
references.citation: Rev Neurosci. 1993 Oct-Dec;4(4):365-72
references.pmid: 8275277
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5150-5
references.pmid: 15788534
references.citation: Peptides. 2005 Nov;26(11):2289-93
references.pmid: 16269354
references.citation: J Neurosci. 2004 Feb 11;24(6):1521-9
references.pmid: 14960625
references.citation: J Cereb Blood Flow Metab. 2009 Sep;29(9):1568-78
references.pmid: 19536071
references.citation: J Mol Neurosci. 2013 Mar;49(3):446-56
references.pmid: 22684620
references.citation: Brain Res. 1984 Jun 8;302(2):347-55
references.pmid: 6610460
references.citation: Brain Res Bull. 2006 Jan 30;68(5):374-8
references.pmid: 16377445
references.citation: J Biol Chem. 2008 Jun 27;283(26):18238-47
references.pmid: 18367451
references.citation: J Mol Neurosci. 2012 Jun;47(2):267-77
references.pmid: 22392152
references.citation: Brain Behav Immun. 2011 Jan;25(1):160-7
references.pmid: 20854891
references.citation: Trends Immunol. 2008 Oct;29(10):479-86
references.pmid: 18775671
references.citation: Cell Mol Life Sci. 2008 Sep;65(17):2702-20
references.pmid: 18516496
references.citation: J Appl Physiol (1985). 2012 Apr;112(8):1410-8
references.pmid: 22323652
references.citation: Am J Physiol. 1996 Oct;271(4 Pt 1):E636-42
references.pmid: 8897850
references.citation: Genesis. 2007 May;45(5):292-9
references.pmid: 17457931
references.citation: Endocrinology. 2008 Jun;149(6):2798-806
references.pmid: 18292187
references.citation: J Appl Physiol (1985). 2013 Mar 15;114(6):734-41
references.pmid: 23329815
references.citation: J Mol Neurosci. 2013 Mar;49(3):523-30
references.pmid: 23180096
references.citation: J Immunol. 1998 Dec 1;161(11):6421-6
references.pmid: 9834134
references.citation: Brain. 2009 Apr;132(Pt 4):889-902
references.pmid: 19293246
references.citation: Ann N Y Acad Sci. 2012 Aug;1264:64-71
references.pmid: 22530983
references.citation: Peptides. 2011 Jul;32(7):1392-9
references.pmid: 21616110
references.citation: Trends Immunol. 2013 Aug;34(8):410-22
references.pmid: 23707039
references.citation: Curr Pharm Des. 2010 Oct;16(30):3390-400
references.pmid: 20726835
references.citation: Eur J Immunol. 2001 May;31(5):1324-32
references.pmid: 11465089
references.citation: Microsc Res Tech. 1995 Oct 15;32(3):215-29
references.pmid: 8527856
references.citation: Neuron. 2009 Jan 29;61(2):213-9
references.pmid: 19186164
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9325-30
references.pmid: 18591671
references.citation: Peptides. 2007 Jun;28(6):1317-30
references.pmid: 17540480