Role of Transporters in Multiple Sclerosis Progression: A New Perspective on Monocyte Function

Multiple sclerosis (MS) is a complex immune-mediated and neurodegenerative disease affecting the central nervous system (CNS). While the exact mechanisms driving MS progression are still being investigated, a new study sheds light on the potential role of ion imbalances and monocyte dysfunction in the transition from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS).

What is NCX1 and Why Does It Matter in MS?
The study focuses on the sodium-calcium exchanger 1 (NCX1), a protein that regulates sodium and calcium levels within cells. NCX1 is found predominantly in CNS microglia and circulating monocytes, and its function can influence cell reactivity during inflammation. Monocytes are a type of white blood cell that can differentiate into macrophages, which are key players in the immune response. In MS, the proinflammatory activity of monocyte-derived macrophages contributes to neurodegeneration.

Key Findings of the Study: Stage-Specific Dysregulation of NCX1 in Monocytes
The researchers investigated the expression of NCX1 in monocytes from patients with RRMS and SPMS. They discovered a stage-specific dysregulation of NCX1 during MS progression:

* Transitional RRMS: NCX1 expression was significantly upregulated in monocytes from RRMS subjects transitioning to SPMS (RRMS with EDSS ≥4). EDSS (Expanded Disability Status Scale) is a method used to quantify disability in multiple sclerosis.

* SPMS: NCX1 expression was significantly reduced in all monocyte subsets after the conversion from RRMS to SPMS.

These findings suggest that NCX1 plays a dynamic role in monocyte function during MS progression.

NCX1 and Regulatory T Cells (Tregs): A Connection to Immune Regulation
The study also found that NCX1 levels in monocytes significantly correlated with the percentage and growth ability of regulatory T cells (Tregs). Tregs are a subset of T cells that suppress immune responses and help maintain immune tolerance. Derangement of Tregs underlies MS progression. This suggests that NCX1 dysregulation in monocytes may affect the immune regulatory network in MS.

The Role of Monocyte Subsets in MS
The researchers further investigated NCX1 expression in different monocyte subsets: classical (CD14+CD16-) and intermediate (CD14+CD16+) monocytes. They found that:

* The percentage of intermediate CD14+CD16+ monocytes increased in RRMS and SPMS.
* NCX1 expression was significantly increased in both monocyte subsets from transitional RRMS subjects (EDSS ≥4).
* Both classical and intermediate monocytes from SPMS donors displayed reduced NCX1 protein levels compared to the RRMS group with EDSS≥4.

These findings highlight the potential importance of monocyte heterogeneity and inter-subset plasticity during MS progression.

NCX1 and Other Ion Transporters: A Complex Interplay
The study also explored the expression of other ion transporters and a long non-coding RNA (lncRNA) in peripheral blood mononuclear cells (PBMCs):

* PBMCs are blood cells with a round nucleus (lymphocytes and monocytes).

* Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides that regulate gene expression.

* Perturbations in transcripts encoding the Ca2+-ATPase isoforms 1 and 4, the Na+/K+-ATPase α1 subunit, and the lncRNA SLC8A1-AS1 were associated with NCX1 changes in PBMCs during MS.

* Ca2+-ATPases are calcium pumps.

* Na+/K+-ATPases are sodium-potassium pumps.

* SLC8A1-AS1 is a lncRNA regulating NCX1.

These findings suggest a complex interplay between NCX1 and other molecules involved in ion homeostasis during MS.

Potential Implications for MS Biomarkers and Therapeutics
This study provides valuable insights into the role of NCX1 and monocyte function in MS progression. The findings suggest that:

* NCX1 could serve as a potential biomarker for monitoring MS progression and identifying patients at risk of transitioning to SPMS.

* Targeting NCX1 or related ion transport mechanisms could offer novel therapeutic strategies for MS.

Limitations and Future Directions
The authors acknowledge several limitations of the study:
* Limited number of patients
* Lack of consideration for sex or disease-modifying therapies (DMTs)
* Lack of functional experiments

Future research should address these limitations and further investigate the mechanistic link between NCX1 levels in monocytes and Treg differentiation.

In Conclusion
This study sheds light on the complex interplay between ion transport, monocyte function, and immune regulation in MS progression. By identifying NCX1 as a key player in this process, the research opens new avenues for developing biomarkers and therapeutic interventions for this debilitating disease.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Rubino, V., Cammarota, M., Criscuolo, C., Cianflone, A., De Martino, M., de Rosa, V., Esposito, F., Abbadessa, G., Carriero, F., Terrazzano, G., Chieffi, P., Bonavita, S., Bresciamorra, V., Annunziato, L., Ruggiero, G., & Boscia, F. (2025). Modulation of NCX1 expression in monocytes associates with multiple sclerosis progression. Heliyon, 11(4), e42332. https://doi.org/10.1016/j.heliyon.2025.e42332