MK2 and Fas Receptor Contribute to the Severity of CNS Demyelination

Models of inflammatory or degenerative diseases demonstrated that the protein-kinase MK2 is a key player in inflammation. In this study we examined the role of MK2 in MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In MK2-deficient (MK2(−/−)) mice we found a delayed onset of the disease and MK2(−/−) mice did not recover until day 24 after EAE induction. At this day a higher number of leukocytes in the CNS of MK2(−/−) mice was found. TNFα was not detectable in serum of MK2(−/−) mice in any stage of EAE, while high TNFα levels were found at day 16 in wild-type mice. Further investigation revealed an increased expression of FasR mRNA in leukocytes isolated from CNS of wild-type mice but not in MK2(−/−) mice, however in vitro stimulation of MK2(−/−) splenocytes with rmTNFα induced the expression of FasR. In addition, immunocomplexes between the apoptosis inhibitor cFlip and the FasR adapter molecule FADD were only detected in splenocytes of MK2(−/−) mice at day 24 after EAE induction. Moreover, the investigation of blood samples from relapsing-remitting multiple sclerosis patients revealed reduced FasR mRNA expression compared to healthy controls. Taken together, our data suggest that MK2 is a key regulatory inflammatory cytokines in EAE and multiple sclerosis. MK2(−/−) mice showed a lack of TNFα and thus might not undergo TNFα-induced up-regulation of FasR. This may prevent autoreactive leukocytes from apoptosis and may led to prolonged disease activity. The findings indicate a key role of MK2 and FasR in the regulation and limitation of the immune response in the CNS.