Increased activity of the NLRP3 inflammasome in immune cells in the blood is a potential biomarker of primary progressive multiple sclerosis (PPMS), according to a new study published in Brain. The finding could also provide new targets for therapeutic intervention.
“Prognostic molecular biomarkers for MS are lacking”, explains Manuel Comabella, who led the study alongside Sunny Malhotra. “Biomarkers are particularly needed for the progressive form of the disease, for which there is no effective therapy.”
The researchers performed RNA sequencing on peripheral blood mononuclear cells and found that the expression of multiple pro-inflammatory genes, including those encoding IL-1β and NLRP3, was higher in participants with PPMS than in participants with other forms of MS and in healthy controls. This finding was replicated with real-time PCR in a second cohort. NLRP3 forms a protein complex called an inflammasome, which mediates secretion of IL-1β.
During a follow-up period, participants with PPMS who had high IL-1β mRNA levels needed walking assistance an average of 11 years earlier than their counterparts with low IL-1β mRNA levels, suggesting that IL-1β expression is a prognostic marker. IL-1β expression was not associated with disease progression in participants with other forms of MS, indicating that the marker could be specific for PPMS.
The authors suggest that this finding could inform the search for new MS therapies. “At present, we are working on the identification of specific NLRP3 inflammasome inhibitors that totally suppress IL-1β secretion and have the potential to become effective treatments by preventing disease progression in patients with PPMS,” concludes Comabella.
Malhotra, S. et al. NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients. Brain https://doi.org/10.1093/brain/awaa084 (2020)
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Lemprière, S. NLRP3 inflammasome activity as biomarker for primary progressive multiple sclerosis. Nat Rev Neurol 16, 350 (2020). https://doi.org/10.1038/s41582-020-0366-y