title: Pro-inflammatory interferon gamma signaling is directly associated with stroke induced neurodegeneration.
abstract: The delayed immune response to stroke is responsible for the increased neural injury that continues to occur after the initial ischemic event. This delayed immune response has been linked to the spleen, as splenectomy prior to middle cerebral artery occlusion (MCAO) is neuroprotective. Interferon gamma (IFNγ) is linked to the splenic response, which enhances neural injury following MCAO. IFNγ activates the expression of the inflammatory chemokine interferon-inducible protein 10 (IP-10). This study was designed to determine the role of IFNγ signaling in the inflammatory response following MCAO. Expression of IP-10 increased in the brain and the spleen following MCAO. Splenectomy inhibited the increase of IP-10 in the brain post-MCAO, while recombinant IFNγ administration to splenectomized rats returned IP-10 levels in the brain to levels found in rats after MCAO only. Systemic administration of an IFNγ neutralizing antibody to MCAO-treated rats reduced infarct volume and IP-10 levels in the brain. T cell infiltration was reduced in the MCAO-damaged brains of IFNγ antibody-treated animals relative to those that received isotype control antibodies. Additionally, inhibiting IFNγ signaling with splenectomy or an IFNγ neutralizing antibody blocked the induction of IP-10 expression and decreased neurodegeneration following MCAO. Targeting this pro-inflammatory pathway following stroke could be a promising stroke therapeutic.
authors.affiliation: Department of Molecular Pharmacology and Physiology, School of Biomedical Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Seifert
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Collier
authors.forename: Cortney B
authors.initials: CB
authors.lastname: Chapman
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Benkovic
authors.forename: Alison E
authors.initials: AE
authors.lastname: Willing
authors.forename: Keith R
authors.initials: KR
authors.lastname: Pennypacker
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
chemical_list: D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; D018836:Inflammation Mediators; D007371:Interferon-gamma
references.citation: Curr Opin Immunol. 2002 Feb;14(1):129-35
references.pmid: 11790543
references.citation: Stroke. 2013 Apr;44(4):1135-43
references.pmid: 23391769
references.citation: Surgery. 2007 Jan;141(1):32-40
references.pmid: 17188165
references.citation: Stroke. 1989 Jan;20(1):84-91
references.pmid: 2643202
references.citation: J Cereb Blood Flow Metab. 2007 Nov;27(11):1798-805
references.pmid: 17392692
references.citation: J Neurosci Res. 2008 Aug 1;86(10):2227-34
references.pmid: 18381759
references.citation: Exp Neurol. 2010 Oct;225(2):341-52
references.pmid: 20637752
references.citation: J Trauma. 2011 Jul;71(1):141-7
references.pmid: 21248654
references.citation: J Biol Chem. 2001 Feb 2;276(5):2986-91
references.pmid: 11110785
references.citation: Brain. 2011 Mar;134(Pt 3):704-20
references.pmid: 21354973
references.citation: J Pediatr Surg. 2003 Oct;38(10):1465-70
references.pmid: 14577069
references.citation: Annu Rev Immunol. 1997;15:749-95
references.pmid: 9143706
references.citation: Brain. 2008 Mar;131(Pt 3):616-29
references.pmid: 18156155
references.citation: Liver. 1996 Jun;16(3):188-94
references.pmid: 8873006
references.citation: J Neurosci Res. 2009 Feb;87(2):333-41
references.pmid: 18924174
references.citation: Transl Stroke Res. 2012 Dec;3(4):473-81
references.pmid: 23956805
references.citation: J Neuroimmune Pharmacol. 2012 Dec;7(4):1017-24
references.pmid: 23054371
references.citation: Brain Res. 1997 Mar 14;751(1):37-46
references.pmid: 9098566
references.citation: Nat Med. 2009 Feb;15(2):192-9
references.pmid: 19169263
references.citation: Brain Res. 2005 Apr 25;1042(1):29-36
references.pmid: 15823250
references.citation: Circulation. 2006 May 2;113(17):2105-12
references.pmid: 16636173
references.citation: J Neuroinflammation. 2011 Oct 31;8:148
references.pmid: 22040257
references.citation: Circ Res. 2010 Nov 26;107(11):1364-73
references.pmid: 20930148
references.citation: Immunol Cell Biol. 2011 Feb;89(2):207-15
references.pmid: 21221121
references.citation: Curr Neurovasc Res. 2006 May;3(2):89-98
references.pmid: 16719792
references.citation: Metab Brain Dis. 2012 Jun;27(2):131-41
references.pmid: 22354752
references.citation: J Cereb Blood Flow Metab. 2006 May;26(5):654-65
references.pmid: 16121126
references.citation: Transl Stroke Res. 2011 Sep;2(3):328-38
references.pmid: 24323652