MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge

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.

A single-cell atlas reveals the heterogeneity of meningeal immunity in a mouse model of Methyl CpG binding protein 2 deficiency

“…MeCP2 is expressed in immune cells. Polymorphisms in MeCP2 have been linked to increased susceptibility to autoimmune diseases, and alterations in MeCP2 expression levels affect immune function and cytokine production ( 3 , 33 ). However, little is known about changes in meningeal immunity in the absence of MeCP2 and the role of meningeal immunity in RTT progression.…”

Comprehensive Transcriptomic Investigation of Rett Syndrome Reveals Increasing Complexity Trends from Induced Pluripotent Stem Cells to Neurons with Implications for Enriched Pathways

“…In studies conducted to examine the impairments in the immune response processes in RTT, MECP2 is reported to affect neuroimmune homeostasis by creating disturbances in the balance between pro/anti-inflammation. Therefore, irregularities are observed in immune activation. , These studies have shown that MECP2 has an important role in regulating monocytes, macrophages, and CD4+ T and B cells.…”

Whole blood vs serum-derived exosomes for host and pathogen-specific tuberculosis biomarker identification: RNA-seq based machine learning approach

“…It is interesting to note the down-regulation of transcriptional regulation by methyl-CpG binding protein 2 (MeCP2) and proline catabolism in EXOs during the active stage. MeCP2 is a protein that plays a crucial role in regulating gene expression through its interaction with methylated DNA (Zalosnik et al 2021). Given MeCP2's role in immune cells and cytokine production (Zalosnik et al 2021), its alteration could in uence immune function during TB infection.…”