EARLY-LIFE EXPOSURE TO LIPOPOLYSACCHARIDE REDUCES THE SEVERITY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN ADULTHOOD AND CORRELATED WITH INCREASED URINE CORTICOSTERONE AND APOPTOTIC CD4  T CELLS Z.-W. WANG, a,b P. WANG, a F.-H. LIN, a X.-L. LI, a X.-F. LI, c K. THOMAS O’BYRNE, c S.-T. HOU a,d * AND R.-Y. ZHENG a * a Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Number 2 Fuxue Lane, Wenzhou City, Zhejing Province 325000, PR China b Department of Neurology, Shaoxing People’s Hospital, 568 Zhonxin Bei Road, Shaoxing City, Zhejiang Province 312000, PR China c Division of Reproduction and Endocrinology, King’s College London, Guy’s Campus, London SE1 1UL, UK d Institute for Biological Sciences, National Research Council of Can- ada, 1200 Montreal Road, Building M54, Ottawa, ON K1A 0R6, Canada Abstract—Early-life exposure to bacterial endotoxins, such as lipopolysaccharides (LPS), can provide neuroprotection against experimental autoimmune encephalomyelitis (EAE) during adulthood, possibly through altering the responsive- ness of the immune system. Here, we show that exposure of LPS to neonatal rats resulted in a sustained elevation of corticosterone level in urine when compared with saline- treated rats, and that the high level of urine corticosterone was maintained during the progression of EAE (P<0.05). This high level of production of corticosterone plays an important role in altering the predisposition to EAE-induced neuroin- flammation, as a positive correlation occurred between the concentration of urine corticosterone and the increased ap- optotic CD4  T cells from the peripheral blood. LPS-treated rats also showed a reduced number of CD3  T cells in the spinal cord. The splenic antigen-presenting cells showed a reduced expression of MHC II during EAE development in LPS-exposed rats when compared with rats exposed to the saline-treated control. Together, these findings suggest that treating neonatal rats with LPS evokes a sustained elevation of glucocorticoid, which may suppress immune response during EAE by increasing apoptosis of CD4  T cells and reducing the expression of MHC II on antigen-presenting cells. Therefore, exposing neonates to bacterial endotoxin may further be developed as an immunization strategy to prevent human multiple sclerosis and other inflammatory brain diseases. Crown Copyright © 2011 Published by Elsevier Ltd on behalf of IBRO. All rights reserved. Key words: experimental autoimmune encephalomyelitis, multiple sclerosis, neuroprotection, lipopolysaccharide, cor- ticosterone, immune regulation. Multiple sclerosis (MS) is a chronic inflammatory autoim- mune disease of the CNS and the most common cause of neurological disability in young adults. Mechanistically, the interplay between susceptibility genes and environmental factors contributes to the pathogenesis of MS (Ramago- palan et al., 2008; Sotgiu et al., 2004). However, currently there is a lack of disease-modifying therapeutic treatment for MS, and management of MS symptoms appears to be the only common clinical practice for treatment (Pittock et al., 2006; Sospedra and Martin, 2005; Thompson et al., 2010; Wingerchuk et al., 2001). Exciting evidence emerged in recent years where mod- ulation of the developmental plasticity of the immune sys- tem early in life can alter the predisposition to inflammation in adulthood. Indeed, helminth infections and more subtle exposure to environmental microbes have been shown to reduce the risk of relapses in MS and also protect the brain during experimental autoimmune encephalomyelitis (EAE), the principal model for MS (La Flamme et al., 2003; Sewell et al., 2003). Several recent studies, including those of our own (Li et al., 2010), also showed that treating neonatal rats during their first week of life with lipopolysac- charide (LPS) significantly suppresses EAE-induced spinal cord damage. The possible mechanisms are through al- tering the activities of hypothalamic-pituitary-adrenal (HPA) axis function, which in turn promotes tolerogenic dendritic cells and regulatory T cells (Ellestad et al., 2009; Wang and McCusker, 2006), and regulates the immune response in the CNS (Li et al., 2010). The neuroendocrine system, such as HPA, plays a critical regulatory role on the immune system (Shanks et al., 1995, 2000). Modulation of the immune system, in turn, triggers the onset and development of EAE. Activation of CD4 + autoreactive T cells and their differentiation into a Th1 phenotype are crucial events in the initial steps. These cells are also important players in the long-term evolution of the disease (Sospedra and Martin, 2005). Stress-in- duced glucocorticoids directly target the HPA and produce a pronounced anti-inflammatory effect. Glucocorticoids may exert their immunosuppressive activity by inducing *Correspondence to: R.-Y. Zheng, Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiol- ogy, Wenzhou Medical College, Number 2 Fuxue Lane, Wenzhou City, Zhejing Province 325000, PR China. Tel: +86(0577)88069311; or S.-T. Hou, Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Road, Building M54, Ottawa, ON K1A 0R6, Canada. Tel: +16139937764. E-mail address: zhengry@yahoo.com.cn (R.-Y. Zheng) or sheng.hou@ nrc-cnrc.gc.ca (S.-T. Hou). Abbreviations: CFA, complete Freund’s adjuvant; EAE, encephalomy- elitis; HPA, hypothalamic-pituitary-adrenal; H&E, hematoxylin-eosin; LPS, lipopolysaccharide; MS, multiple sclerosis; SCH, spinal cord homogenate. Neuroscience 193 (2011) 283–290 0306-4522/11 $ - see front matter. Crown Copyright © 2011 Published by Elsevier Ltd on behalf of IBRO. All rights reserved. doi:10.1016/j.neuroscience.2011.07.047 283