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

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. © 2011 zhao et al; licensee biomed central ltd.