MK2 and Fas receptor contribute to the severity of CNS demyelination

• Published in: PloS one 2014-06, Vol.9 (6), p.e100363
• Main Authors: Tietz, Silvia M, Hofmann, Regina, Thomas, Tobias, Tackenberg, Björn, Gaestel, Matthias, Berghoff, Martin
• Format: Article
• Language: English
• Subjects: Adapters; Adult; Analysis; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Autoimmune diseases; Autoimmunity; Biology and Life Sciences; c-FLIP protein; Cell Count; Central nervous system; Central Nervous System - immunology; Central Nervous System - metabolism; Cytokines; Degenerative diseases; Demyelination; Encephalomyelitis, Autoimmune, Experimental - blood; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Experimental allergic encephalomyelitis; FADD protein; fas Receptor - blood; fas Receptor - genetics; fas Receptor - metabolism; Female; Gene expression; Humans; Immune response; Immune system; Inflammation; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Leukocytes; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes - metabolism; Male; Medicine and Health Sciences; Mice; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple Sclerosis - physiopathology; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - metabolism; Recurrence; Research and Analysis Methods; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Spleen - cytology; Splenocytes; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Up-Regulation - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100363

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 MOG35-55-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.