Thesis
The role of map kinase phosphatase 2 (MKP-2) in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2015
- Thesis identifier
- T14113
- Person Identifier (Local)
- 201189504
- Qualification Level
- Qualification Name
- Department, School or Faculty
- 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. 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.
- Resource Type
- DOI
- Date Created
- 2015
- Former identifier
- 1237429
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