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

Abstract

Methyl CpG binding protein 2 (MeCP2) is a DNA methylation reader protein. Mutations in MeCP2 are the major cause of Rett syndrome (RTT). Increasing evidence has shown that dysregulated immunity and chronic subclinical inflammation are linked to MeCP2 deficiency and contribute to RTT development and deterioration. The meninges surrounding the central nervous system (CNS) contain a wide repertoire of immune cells that participate in immune surveillance within the CNS and influence various brain functions; however, the characterization and role of meningeal immunity in CNS with MeCP2 deficiency remain poorly addressed. Here, we used single-cell sequencing to profile Mecp2-deficient meningeal immune cells from the dura mater, which has been reported to contain the most meningeal immune cells during homeostasis. Data showed that the meninges of Mecp2-null mice contained the same diverse immune cell populations as control mice and showed an up-regulation of immune-related processes. B cell populations were greater in Mecp2-null mice than in control mice, and the expression of genes encoding for immunoglobulins was remarkably higher. Mecp2-deficient meninges also contained more cytotoxic CD8+ T cells than control meninges. With increased interferon-γ transcription in T and natural killer cells, meningeal macrophages showed decreased suppression and increased activity in Mecp2-deficienct mice. Together, these findings provide novel insights into meningeal immunity, which is a less studied aspect of neuroimmune interactions in Mecp2-mutated diseases, and offer an essential resource for comparative analyses and data exploration to better understand the functional role of meningeal immunity in RTT.

Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway

“…In RTT, reduced IFNγ concentration was demonstrated in patients’ serum (Leoncini et al, 2015), but single cell sequencing analysis of meningeal immune cells reported an increased IFNγ expression in KO mice (Li et al, 2023). While our data demonstrate that NPCs strongly activate IFNγ response pathway in the cerebellum of KO animals, they do not provide details regarding the source of the cytokine, since both NPCs and resident immune cells might concur to the activation of the cytokine pathway (Cossetti et al, 2014; Monteiro et al, 2017).…”