title: Neuroimmune modulation following traumatic stress in rats: evidence for an immunoregulatory cascade mediated by c-Src, miRNA222 and PAK1.
abstract: BACKGROUND
  Neuroimmune modulation following traumatic stress is accompanied by cortical upregulation of c-Src expression, but the mechanistic details of the potential regulatory link between c-Src expression and immunosuppression have not been established.
  
  
  METHODS
  We used a combination of techniques to measure temporal changes in: (i) the parallel expression of c-Src and microRNA222; (ii) levels of PAK1 (p21-activated kinase 1); and (iii) the association between PAK1 and interleukin 1β signaling, both in cortex of rats following traumatic stress and in primary cortical neurons. Techniques included real-time PCR, immunoprecipitation, western blotting and subcellular fractionation by discontinuous centrifugation. We also measured lymphocyte proliferation and natural killer (NK) cell activity.
  
  
  RESULTS
  We confirm robust upregulation of c-Src expression following traumatic stress. c-Src upregulation was accompanied by marked increases in levels of miRNA222; other studied miRNAs were not affected by stress. We also established that PAK1 is a primary target for miRNA222, and that increased levels of miRNA222 following traumatic stress are accompanied by downregulation of PAK1 expression. PAK1 was shown to mediate the association of IL-1RI with lipid rafts and thereby enhance IL-1 signaling. Detailed analyses in cultured neurons and glial cells revealed that PAK1-mediated enhancement of IL-1RI activation is governed to a large extent by c-Src/miRNA222 signaling; this signaling played a central role in the modulation of lymphocyte proliferation and NK cell activity.
  
  
  CONCLUSIONS
  Our results suggest that neuroimmune modulation following traumatic stress is mediated by a cascade that involves c-Src-mediated enhancement of miRNA222 expression and downregulation of PAK1, which in turn impairs signaling via IL-1β/IL1-RI, leading to immunosuppression. The regulatory networks involving c-Src/miRNA222 and PAK1/IL-1RI signaling have significant potential for the development of therapeutic approaches designed to promote recovery following traumatic injury.
authors.affiliation: Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College, Brain Research Institute, Fudan University, Shanghai, P R China. zhaohui07054@fudan.edu.cn
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Ranran
authors.initials: R
authors.lastname: Yao
authors.forename: Xiaoding
authors.initials: X
authors.lastname: Cao
authors.forename: Gencheng
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004789:Enzyme Activation; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D014947:Wounds and Injuries / Q000276:immunology* / Q000503:physiopathology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: D053583:Interleukin-1beta; C568897:MIRN222 microRNA, rat; D035683:MicroRNAs; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D054462:p21-Activated Kinases
references.citation: Ann Hematol. 2009 Nov;88(11):1059-67
references.pmid: 19290526
references.citation: Immunity. 2009 Jun 19;30(6):817-31
references.pmid: 19481478
references.citation: FEBS Lett. 1997 Feb 10;403(1):23-5
references.pmid: 9038353
references.citation: Cell Signal. 2006 Oct;18(10):1679-84
references.pmid: 16497477
references.citation: Trends Mol Med. 2011 Oct;17(10):548-55
references.pmid: 21813326
references.citation: J Neurosci. 2009 May 20;29(20):6649-62
references.pmid: 19458235
references.citation: Neuropharmacology. 2009 Jan;56(1):73-80
references.pmid: 18644395
references.citation: J Cell Sci. 2010 Mar 1;123(Pt 5):712-22
references.pmid: 20144995
references.citation: Neurobiol Aging. 1997 May-Jun;18(3):343-8
references.pmid: 9263201
references.citation: Biochemistry. 2008 May 27;47(21):5681-5688
references.pmid: 18444664
references.citation: Neuroscience. 2000;101(4):957-67
references.pmid: 11113345
references.citation: Synapse. 2011 May;65(5):433-40
references.pmid: 20853446
references.citation: PLoS One. 2009 Oct 27;4(10):e7607
references.pmid: 19859555
references.citation: J Biol Chem. 1996 Apr 19;271(16):9690-7
references.pmid: 8621645
references.citation: Mol Cell. 2010 May 14;38(3):323-32
references.pmid: 20471939
references.citation: J Cell Sci. 2010 Jul 1;123(Pt 13):2256-65
references.pmid: 20530578
references.citation: Immunity. 2009 Dec 18;31(6):965-73
references.pmid: 20005135
references.citation: Neuroscience. 2002;114(4):1019-31
references.pmid: 12379256
references.citation: BMC Immunol. 2009 Mar 19;10:15
references.pmid: 19298660
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Jul;299(1):G186-95
references.pmid: 20378826
references.citation: J Neurosci. 2007 Aug 8;27(32):8604-15
references.pmid: 17687038
references.citation: Sheng Li Xue Bao. 2001 Jun;53(3):209-14
references.pmid: 12589406
references.citation: J Neurosci. 2000 Jan 1;20(1):149-55
references.pmid: 10627591
references.citation: Cell Signal. 2009 Mar;21(3):384-93
references.pmid: 19036346
references.citation: Eur Cytokine Netw. 2008 Mar;19(1):1-7
references.pmid: 18299267
references.citation: Neuroscience. 2010 Jan 13;165(1):107-15
references.pmid: 19819308
references.citation: Philos Trans R Soc Lond B Biol Sci. 2007 May 29;362(1481):917-32
references.pmid: 17412678
references.citation: Cancer Res. 2008 Oct 15;68(20):8195-200
references.pmid: 18922890
references.citation: Biochem Biophys Res Commun. 2010 Jun 11;396(4):1042-7
references.pmid: 20471961
references.citation: Acta Biomed. 2007;78 Suppl 1:231-47
references.pmid: 17465337
references.citation: J Neuroimmunol. 2000 Sep 22;109(2):164-72
references.pmid: 10996218
references.citation: J Cell Mol Med. 2007 Jul-Aug;11(4):810-25
references.pmid: 17760842
references.citation: Oncogene. 2009 Dec 3;28(48):4272-83
references.pmid: 19767772
references.citation: J Neurosci. 2003 Sep 24;23(25):8692-700
references.pmid: 14507968
references.citation: Genes Dev. 2010 Jun 1;24(11):1086-92
references.pmid: 20516194
references.citation: Brain Res. 2009 Feb 19;1255:162-9
references.pmid: 19109931
references.citation: Blood Purif. 2009;28(1):12-4
references.pmid: 19325234
references.citation: Pharmacol Rev. 1991 Sep;43(3):299-349
references.pmid: 1956954
references.citation: Front Neuroendocrinol. 2009 Jan;30(1):30-45
references.pmid: 19017533
references.citation: J Biol Chem. 2005 Feb 11;280(6):4279-88
references.pmid: 15561713
references.citation: J Vasc Res. 2009;46(6):527-40
references.pmid: 19571573
references.citation: Int J Oncol. 2010 Apr;36(4):913-20
references.pmid: 20198336
references.citation: Glia. 2005 Jan 15;49(2):161-76
references.pmid: 15472994
references.citation: J Mol Neurosci. 2010 Jan;40(1-2):47-55
references.pmid: 19711202
references.citation: Mol Med. 2000 Dec;6(12):1028-41
references.pmid: 11474119
references.citation: Cereb Cortex. 2009 Apr;19(4):861-75
references.pmid: 18701438
references.citation: Dev Neurobiol. 2007 Apr;67(5):655-69
references.pmid: 17443815