Abstract
Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene. It has been suggested that immune alterations may play an active role in the generation and/or maintenance of RTT phenotypes. However, there is no clear consensus about which pathways are regulated in vivo by MeCP2 in the context of immune activation. In the present work we set to characterize the role of MeCP2 during the progression of Experimental Autoimmune Encephalomyelitis (EAE) using the MeCP2308/y mouse model (MUT), which represents a condition of “MeCP2 function deficiency”. Our results showed that MeCP2 deficiency increased the susceptibility to develop EAE, along with a defective induction of anti-inflammatory responses and an exacerbated MOG-specific IFNγ expression in immune sites. In MUT-EAE spinal cord, we found a chronic increase in pro-inflammatory cytokines gene expression (IFNγ, TNFα and IL-1β) and downregulation of genes involved in immune regulation (IL-10, FoxP3 and CX3CR1). Moreover, our results indicate that MeCP2 acts intrinsically upon immune activation, affecting neuroimmune homeostasis by regulating the pro-inflammatory/anti-inflammatory balance in vivo. These results are relevant to identify the potential consequences of MeCP2 mutations on immune homeostasis and to explore novel therapeutic strategies for MeCP2-related disorders.
Highlights
Rett syndrome is a severe and progressive neurological disorder linked to mutations in the Methyl-CpG binding protein 2 (MeCP2) gene
Our results suggest that MeCP2 acts intrinsically upon immune activation, affecting neuroimmune homeostasis by regulating the pro-inflammatory/anti-inflammatory balance in vivo
All MeCP2-MUT mice injected with MOG developed EAE clinical signs; in contrast, only 84% of WT mice develop EAE (WT mice that did not develop the disease were discarded from subsequent analyses)
Summary
Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene. Our results indicate that MeCP2 acts intrinsically upon immune activation, affecting neuroimmune homeostasis by regulating the proinflammatory/anti-inflammatory balance in vivo. A wealth of evidence indicates that redox imbalance, mitochondrial dysfunction, immune alterations and systemic subclinical inflammation are crucial players in a process coined “oxInflammation” that strongly affects clinical progression in RTT p atients[21,22,23,24,25,26,27] All these data suggest that Mecp[2] mutations may affect the immune homeostasis and it is reasonable to consider that the immune system may play an active role in the generation and/or maintenance of RTT alterations. From a potentially translational point of view, the interpretation of these results is complex in the context of RTT and associated disorders, in which MeCP2 protein is expressed, at lower levels or as a functionally deficient protein
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