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bioRxiv · 10.1101/2020.08.05.238683

MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge: implications for Rett Syndrome.

Zalosnik, M. I.·Fabio, M. C.·Bertoldi, M. L.·Castanares, C. N.·Degano, A. L.
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Abstract

Background: Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene located on the X chromosome. So far it has not been established how the presence of a mutant form of MeCP2 can maintain essential regulation of immune responses to support the normal homeostasis of individuals. Since MeCP2 is mostly expressed as a "partially functional" protein in humans with RTT, the aim of our work was to evaluate whether a mutation in MeCP2 interferes with the induction of neuroinflammatory responses in real time. Methods: We used MeCP2308/y mouse model (MUT) and exposed it to an autoimmune challenge, experimental autoimmune encephalomyelitis (EAE). WT and MUT mice were immunized with CFA-MOG or CFA alone (control) and clinical scores were evaluated daily. Animals were sacrificed at either 12 days post-induction (dpi, acute stage) or 30 dpi (chronic stage) and spleen and spinal cord were collected from individual mice for further studies. Cellular infiltration and microgliosis was evaluated by IHC. Cytokine production was assessed in spinal cord and in cultured splenocytes after MOG activation ex-vivo by cytometry and real time RT-PCR. Results: 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 reactivity with high IFN{gamma} expression in peripheral immune sites. During the chronic stage, an increase in gene expression of pro-inflammatory cytokines (IFN{gamma}, TNF and IL-1{beta}) and downregulation of genes relevant for immune regulation (IL-10, FoxP3 and CX3CR1) was found in MUT-EAE spinal cords. Conclusions: This is the first study performed in a MeCP2 mutant mouse model that explores the pathophysiology and neuroinflammation in the context of an autoimmune challenge. We could establish that an MeCP2 mutation act intrinsically affecting neuroimmune interactions by promoting an inflammatory environment and a deficient immune regulatory setting. These results are relevant for understanding the consequences of MeCP2 mutations on immune homeostasis in MeCP2-related disorders, as well as setting the bases for further therapeutic interventions that consider the immune status in patients.

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Zalosnik, M. I., Fabio, M. C., Bertoldi, M. L., Castanares, C. N., Degano, A. L.. 2020-08-06. MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge: implications for Rett Syndrome.. https://doi.org/10.1101/2020.08.05.238683

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