Longitudinal changes in the expression of IL-33 and IL-33 regulated genes in relapsing remitting MS
Subramaniam Sriram1, Guzel Shaginurova2,3, John T Tossberg3
1Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
Objective:
We tested the hypothesis that the expression of IL-33 in MS is dynamic and is likely to reflect the clinical and radiological changes during the course of RRMS.
Methods:
MS with either clinical or radiological relapses were recruited for the study and followed for one year. IL-33 and a panel of genes was measured by q PCR and flow cytometry at different time points.
Results:
Among 22 RRMS patients, 4 patients showed highest levels of IL-33 at the time they were recruited to the study (Month 0); in 14 patients highest levels of IL-33 were seen between 6-11 months after relapse and in 4 patients maximal levels of IL-33 were seen 12 months after relapse. A similar pattern of IL-33 kinetics was seen when IL-33 was measured by flow cytometry in an additional cohort of 12 patients. The timing of the improvement clinically did not correlate with IL-33 expression with highest expression levels either preceding or following clinical recovery. From our whole genome RNA-sequencing data we found a strong correlation between expression levels of IL-33 and a ~2000 mRNA genes. However, none of these genes encoded proteins involved in either innate or adaptive immunity. Rather, many of the genes that correlated highly with IL-33 encoded to proteins involved in DNA repair or mitochondrial function and mRNA splicing pathways.
Interpretation:
Given the neuro-reparative and remodeling functions attributed to IL-33, it is likely that some of the novel genes we have uncovered may be involved in repair and recovery of the CNS in MS.
Insights
Interleukin-33 (IL-33) levels in multiple sclerosis (MS) fluctuate over time and correlate with genes involved in DNA repair and mitochondrial function, suggesting a role in central nervous system (CNS) repair.
Area of Science:
- Neuroimmunology
- Genetics
- Molecular Biology
Background:
- Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS).
- The role of Interleukin-33 (IL-33) in MS pathogenesis and recovery is not fully understood.
- Understanding dynamic changes in immune markers like IL-33 may offer insights into disease course and repair mechanisms.
Purpose of the Study:
- To investigate the dynamic expression patterns of IL-33 in relapsing-remitting MS (RRMS).
- To correlate IL-33 expression kinetics with clinical and radiological changes in RRMS patients.
- To identify genes co-expressed with IL-33 and explore their potential functions in CNS repair.
Main Methods:
- Longitudinal study of 22 RRMS patients over one year.
- Measurement of IL-33 and gene expression using quantitative PCR and flow cytometry.
- Whole genome RNA-sequencing to identify co-expressed genes.
Main Results:
- IL-33 expression levels varied significantly over the one-year study period in RRMS patients.
- Peak IL-33 levels were observed at different time points relative to relapse, with no direct correlation to clinical improvement timing.
- IL-33 expression strongly correlated with approximately 2000 mRNA genes, many involved in DNA repair, mitochondrial function, and mRNA splicing, rather than immune pathways.
Conclusions:
- IL-33 expression in RRMS is dynamic and does not directly track clinical recovery.
- The identified co-expressed genes suggest a potential role for IL-33 in neuro-reparative processes within the CNS.
- Further research into these novel IL-33-associated genes may uncover new therapeutic targets for CNS repair in MS.
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