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PDF of thesis T14113 PDF of thesis T14113 - (4 M)
Title The role of map kinase phosphatase 2 (MKP-2) in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis / by Mark J. Barbour.
Name Barbour, Mark J. .
Abstract Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), causing a demyelinating central nervous system (CNS) inflammation which resembles the main pathological features of MS. Mitogen-activated protein kinases (MAPKs), which are key components in the molecular response leading to MS/EAE pathogenesis, are regulated by MAPK phosphatases (MKPs), enzymes which dephosphorylate phosphotyrosine and phosphothreonine residues. It has previously been shown that MKP-2 modulates the inflammatory response during both acute lung injury and sepsis. Therefore in the present study we investigated the role of MKP-2 in the development of the neurological autoimmune disease, MS, using a murine EAE model. We first observed significantly increased expression of MKP-2 mRNA in the spinal cord of EAE mice compared with PBS controls. Subsequently, to understand the function of MKP-2 in vivo, we utilised MKP-2 deficient mice, inducing EAE in MKP-2 KO and WT littermates. Our data show that MKP-2 KO mice displayed significantly reduced EAE susceptibility, associated with diminished CNS inflammation and cellular infiltration, decreased expression of key cytokines and chemokines (IL-17, IFNγ, IL-6, IL-2 and CCL2), reduced frequency of CD4⁺ T cells, CD8⁺ T cells and B cells in spleen and dLN tissue as well as downregulated nitric oxide (NO) production in MKP-2 KO EAE mice. We further analysed the role of MKP-2 in two key immune cells involved in EAE pathogenesis. Upon LPS stimulation, MKP-2 deficient bone marrow-derived dendritic cells expressed less MHC-II while producing more IL-6, TNF-α and IL-10, whereas MKP-2 KO bone marrow-derived macrophages displayed a unique M1 and M2 mixed phenotype, with reduced NO production (M1) and increased CD206 expression (M2) but increased IL-6 and TNF-α, which are more associated with M1 responses.
Abstract Therefore this report suggests that MKP-2 is essential to the pathogenic response of EAE, and that inhibition of MKP-2 expression or function may be a viable strategy in the treatment of autoimmune inflammatory diseases such as MS.
Publication date 2015
Name University of Strathclyde. Strathclyde Institute of Pharmacy and Biomedical Sciences.
Thesis note Thesis PhD University of Strathclyde 2015 T14113
System Number 000004224

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