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.
|Date of Award||2 Oct 2015|
- University Of Strathclyde
|Sponsors||EPSRC (Engineering and Physical Sciences Research Council)|
|Supervisor||Hui-Rong Jiang (Supervisor) & Robin Plevin (Supervisor)|