Neuroimmune modulation following traumatic stress in rats: evidence for an immunoregulatory cascade mediated by c-Src, miRNA222 and PAK1

Journal of Neuroinflammation

Gencheng Wu¹  Xiaoding Cao¹  Ranran Yao¹  Hui Zhao¹ 

[1] Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College, Brain Research Institute, Fudan University, Shanghai, P. R. China

关键词: neuroimmune modulation;    IL-1β;    PAK-1;    miRNA222;    c-Src;   

Others  :  1213005
DOI  :  10.1186/1742-2094-8-159

 received in 2011-09-05, accepted in 2011-11-14,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Zhao et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Goshen I, Yirmiya R: Interleukin-1 (IL-1): A central regulator of stress responses. Front Neuroendocrinol 2009, 30:30-45.
• [2]Stahel PF, Kariya K, Shohami E, Barnum SR, Eugster HP, Trentz O, Kossmann T, Morganti-Kossmann MC: Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-a following closed head injury in mice. J Neuroimmunol 2000, 109:164-172.
• [3]Ginis I, Hallenbeck JM, Liu J, Spatz M, Jaiswal R, Shohami E: Tumor necrosis factor and reactive oxygen species cooperative cytotoxicity is mediated via inhibition of NF-κB. Mol Med 2000, 6:1028-1041.
• [4]Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, Soreq H: MicroRNA-132 Potentiates Cholinergic Anti-Inflammatory Signaling by Targeting Acetylcholinesterase. Immunity 2009, 31:965-973.
• [5]Zhao H, Du LN, Jiang JW, Wu GC, Cao XD: Modulatory effect of orphanin FQ on the IL-1beta transcripts in hippocampus. Sheng Li Xue Bao 2001, 53:209-214.
• [6]John GR, Lee SC, Song X, Rivieccio M, Brosnan CF: IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 2005, 49:161-176.
• [7]Agay D, Andriollo-Sanchez M, Claeyssen R, Touvard L, Denis J, Roussel AM, Chancerelle Y: Interleukin-6, TNF-alpha and interleukin-1 beta levels in blood and tissue in severely burned rats. Eur Cytokine Netw 2008, 19:1-7.
• [8]Murray CA, McGahon B, McBennett S, Lynch MA: Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats. Neurobiol Aging 1997, 18:343-348.
• [9]Konsman JP, Tridon V, Dantzer R: Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS. Neuroscience 2000, 101:957-67.
• [10]Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, Griffin WS: Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci 2000, 20:149-55.
• [11]Zhao H, Huang HW, Wu GC, Cao XD: Effect of orphanin FQ on interleukin-1 beta mRNA transcripts in the rat CNS. Neuroscience 2002, 114:1019-1031.
• [12]Oprica M, Hjorth E, Spulber S, Popescu BO, Ankarcrona M, Winblad B, Schultzberg M: Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist. J Cell Mol Med 2007, 11:810-825.
• [13]Smith DE, Lipsky BP, Russell C, Ketchem RR, Kirchner J, Hensley K, Huang Y, Friedman WJ, Boissonneault V, Plante MM, Rivest S, Sims JE: A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1. Immunity 2009, 30:817-831.
• [14]Xiao S, Wang J, Jiang JW, Cao XD, Wu GC, Zhao H: Characterization of Fyn signaling on the age-dependent immunomodulation on traumatic rats. Brain Res 2009, 1255:162-169.
• [15]Basuroy S, Dunagan M, Sheth P, Seth A, Rao RK: Hydrogen peroxide activates focal adhesion kinase and c-Src by a phosphatidylinositol 3 kinase-dependent mechanism and promotes cell migration in Caco-2 cell monolayers. Am J Physiol Gastrointest Liver Physiol 2010, 299:G186-95.
• [16]Takino T, Tsuge H, Ozawa T, Sato H: MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimensional collagen matrix. Biochem Biophys Res Commun 2010, 396:1042-7.
• [17]Li X, Shen Y, Ichikawa H, Antes T, Goldberg GS: Regulation of miRNA expression by Src and contact normalization: effects on nonanchored cell growth and migration. Oncogene 2009, 28:4272-83.
• [18]Meerson A, Cacheaux L, Goosens KA, Sapolsky RM, Soreq H, Kaufer D: Changes in brain microRNAs contribute to cholinergic stress reactions. J Mol Neurosci 2010, 40:47-55.
• [19]Soreq H, Wolf Y: NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol Med 2011, 17:548-555.
• [20]Zhang J, Han L, Ge Y, Zhou X, Zhang A, Zhang C, Zhong Y, You Y, Pu P, Kang C: miR-221/222 promote malignant progression of glioma through activation of the Akt pathway. Int J Oncol 2010, 36:913-20.
• [21]Cardinali B, Castellani L, Fasanaro P, Basso A, Alemà S, Martelli F, Falcone G: Microrna-221 and microrna-222 modulate differentiation and maturation of skeletal muscle cells. PLoS One 2009, 4:e7607.
• [22]Asrar S, Meng Y, Zhou Z, Todorovski Z, Huang WW, Jia Z: Regulation of hippocampal long-term potentiation by p21-activated protein kinase 1 (PAK1). Neuropharmacology 2009, 56:73-80.
• [23]Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M: Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 2003, 23:8692-8700.
• [24]Bergamaschi A, Corsi M, Garnier MJ: Synergistic effects of cAMP-dependent signalling pathways and IL-1 on IL-6 production by H19-7/IGF-IR neuronal cells. Cell Signal 2006, 18:1679-1684.
• [25]Walaas SI, Greengard P: Protein phosphorylation and neuronal function. Pharmacological Reviews 1991, 43:299-349.
• [26]Zhou L, Yan C, Gieling RG, Kida Y, Garner W, Li W, Han YP: Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated Kinase-1. BMC Immunol 2009, 10:15.
• [27]Robbins TW: Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos Trans R Soc Lond B Biol Sci 2007, 362:917-932.
• [28]Hopkins SJ: Central nervous system recognition of peripheral inflammation: a neural, hormonal collaboration. Acta Biomed 2007, 78(Suppl 1):231-247.
• [29]Tsirpanlis G: Cellular senescence and inflammation: a noteworthy link. Blood Purif 2009, 28:12-14.
• [30]Song KS, Li SW, Okamoto T, Quilliam LA, Sargiacomo M, Lisanti MP: Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. A detergent-free purification of caveolae microdomains. J Biol Chem 1996, 271:9690-9697.
• [31]Li X, Shen Y, Ichikawa H, Antes T, Goldberg GS: Regulation of miRNA expression by Src and contact normalization: effects on nonanchored cell growth and migration. Oncogene 2009, 28:4272-83.
• [32]Zhao H, Xiao S, Kong X, Wang J, Cao XD, Wu GC, Loh HH, Law PY: Neuron-glial cell communication in the traumatic stress-induced immunomodulation. Synapse 2011, 65:433-440.
• [33]Cooper JA, Qian H: A mechanism for SRC kinase-dependent signaling by noncatalytic receptors. Biochemistry 2008, 47:5681-5688.
• [34]Endo M, Yamashita T: Inactivation of Ras by p120GAP via focal adhesion kinase dephosphorylation mediates RGMa-induced growth cone collapse. J Neurosci 2009, 29:6649-62.
• [35]Martinez-Rico C, Pincet F, Thiery JP, Dufour S: Integrins stimulate E-cadherin-mediated intercellular adhesion by regulating Src-kinase activation and actomyosin contractility. J Cell Sci 2010, 123:712-22.
• [36]Messa M, Congia S, Defranchi E, Valtorta F, Fassio A, Onofri F, Benfenati F: Tyrosine phosphorylation of synapsin I by Src regulates synaptic-vesicle trafficking. J Cell Sci 2010, 123:2256-65.
• [37]Khanna S, Roy S: Micromanaging vascular biology: tiny microRNAs play big band. Sen CK, Gordillo GM, J Vasc Res 2009, 46:527-40.
• [38]Hussein K, von Neuhoff N, Büsche G, Buhr T, Kreipe H, Bock O: Opposite expression pattern of Src kinase Lyn in acute and chronic haematological malignancies. Ann Hematol 2009, 88:1059-67.
• [39]Newman MA, Hammond SM: Emerging paradigms of regulated microRNA processing. Genes Dev 2010, 24:1086-92.
• [40]Reddy SD, Ohshiro K, Rayala SK, Kumar R: MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer Res 2008, 68:8195-200.
• [41]Siomi H, Siomi MC: Posttranscriptional regulation of microRNA biogenesis in animals. Mol Cell 2010, 38:323-32.
• [42]Hayashi K, Ohshima T, Hashimoto M, Mikoshiba K: Pak1 regulates dendritic branching and spine formation. Dev Neurobiol 2007, 67:655-69.
• [43]Causeret F, Terao M, Jacobs T, Nishimura YV, Yanagawa Y, Obata K, Hoshino M, Nikolic M: The p21-activated kinase is required for neuronal migration in the cerebral cortex. Cereb Cortex 2009, 19:861-75.
• [44]Jacobs T, Causeret F, Nishimura YV, Terao M, Norman A, Hoshino M, Nikolić M: Localized activation of p21-activated kinase controls neuronal polarity and morphology. J Neurosci 2007, 27:8604-15.
• [45]Clerk A, Sugden PH: Activation of p21-activated protein kinase alpha (alpha PAK) by hyperosmotic shock in neonatal ventricular myocytes. FEBS Lett 1997, 403:23-5.
• [46]Basak C, Pathak SK, Bhattacharyya A, Mandal D, Pathak S, Kundu M: NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. J Biol Chem 2005, 280:4279-88.
• [47]Demyanenko GP, Halberstadt AI, Rao RS, Maness PF: CHL1 cooperates with PAK1-3 to regulate morphological differentiation of embryonic cortical neurons. Neuroscience 2010, 165:107-15.
• [48]Kreis P, Barnier JV: PAK signalling in neuronal physiology. Cell Signal 2009, 21:384-93.