MeCP2 Protein’s Lack May Be Driver of Neuroinflammation in Patients

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The lack of a working MeCP2 protein — the most common cause of Rett syndrome — skews the immune system toward a proinflammatory state in the central nervous system (CNS, brain and spinal cord), a study in mice suggests.

According to its scientists, this finding helps in understanding the consequences of MECP2 gene mutations on immune function, and may aid in developing new approaches to treat disorders associated with changes in this gene.

The study, “MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge,” was published in the journal Scientific Reports.

The MECP2 gene, which contains the instructions for the MeCP2 protein, has been reported to regulate nerve cell function and communication.

Most research on this protein has focused on its role in the CNS, where it is particularly abundant. But MeCP2 is active in other tissues, with genetic variants linked with an increased risk for autoimmune diseases, such as systemic lupus erythematosus, thyroid diseases and primary Sjogren’s syndrome.  (Autoimmune disorders are characterized by the immune reactions against healthy tissues.)

Additional evidence suggests that MeCP2 protein levels can affect immune cells, while other studies reported changes in immune markers seen in samples from Rett patients.

These findings led a group of researchers at the Universidad Nacional de Córdoba, Argentina, to wonder if the immune system, via alteration in the MECP2 gene, could contribute to Rett syndrome’s development and progression.

To test this hypothesis, they used a mouse model of Rett carrying a functionally deficient MeCP2 protein. This is more in line with Rett patients than prior approaches in mice, where the MeCP2 protein is completely absent.

To characterize autoimmune response and associated neuroinflammation, the researchers induced experimental autoimmune encephalomyelitis (EAE) in the mice. EAE is a common research model of inflammatory disease with loss of myelin — the fatty coating of nerve fibers.

The researchers found that mice engineered to mimic Rett had a significantly higher susceptibility to develop EAE: all these mice developed EAE symptoms, compared with 84% of EAE mice with normal MeCP2 protein levels, serving as a control group.

Rett mice also developed EAE earlier and showed more severe symptoms, with a slower motor function recovery, when compared with controls.

Next, the researchers investigated how the mutant MeCP2 protein affected inflammation throughout EAE progression.

During its acute phase, immune cells in the Rett mice produced significantly higher levels of two molecules (cytokines) implicated in inflammation — called interleukin (IL)-2 and IL-4 — and lower levels of the anti-inflammatory IL-10.

Further analysis of the acute phase of EAE revealed that the immune system in Rett mice was skewed toward an inflammation-promoting cytokine profile known as the Th1 pro-inflammatory profile. (Interferon gamma is the main Th1 cytokine.)

Cytokine production by spleen cells isolated during the chronic stage of EAE was then analyzed. Results showed that EAE triggered the production of pro-inflammatory cytokines — interferon (IFN) gamma, TNF alpha, IL-6 and IL-17 – in both Rett and control mice.

However, the increase of INF gamma was significantly higher in the Rett-EAE mice than in controls. The decline in INF gamma and TNF alpha during the chronic phase of EAE was also greater in immune cells from control mice relative to Rett mice.

A hallmark of EAE is the infiltration of the CNS, particularly the spinal cord, with immune cells.

Analysis of spinal cord tissue from Rett mice showed significantly higher levels of immune cell infiltration during the acute EAE phase than in control mice.

But during EAE’s chronic stage, the level of immune cell infiltration was lower, and no differences were seen between the two groups of mice.

“These results suggest that MeCP2 mutation facilitates the infiltration of immune cells in the CNS during the acute EAE phase,” the scientists wrote.

The team also found that Rett mice with EAE had higher messenger RNA (mRNA) levels of certain pro-inflammatory cytokines — IFN gamma, TNF alpha and IL-1beta — in the spinal cord than was evident in control mice. mRNA is an intermediate molecule made from DNA and with information to produce proteins.

Spinal cord levels of the CX3CR1 receptor — a protein that regulates the movement of immune cells during EAE progression — and of the regulatory immune T-cells marker Foxp3 were also significantly higher in control mice than in Rett mice developing EAE.

Overall, these findings support the potential role of MeCP2 in the immune system, namely “by regulating the pro-inflammatory/anti-inflammatory balance,” the researchers wrote.

“These results are relevant to identify the potential consequences of MeCP2 mutations on immune homeostasis [equilibrium] and to explore novel therapeutic strategies for MeCP2-related disorders,” they concluded.