| Popis: |
Background: Inflammasomes are involved in the pathogenesis of different neuroimmune and neurodegenerative diseases, including multiple sclerosis (MS). In a previous study by our group, the nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain containing 3 (NLRP3) inflammasome was reported to be associated with the response to interferon-beta in MS. Based on recent data showing the potential for the oral therapy fingolimod to inhibit NLRP3 inflammasome activation, here we investigated whether fingolimod could also be implicated in the response to this therapy in MS patients. Methods: NLRP3 gene expression levels were measured by real-time PCR in peripheral blood mononuclear cells at baseline and after 3, 6, and 12 months in a cohort of MS patients treated with fingolimod (N=23), dimethyl fumarate (N=21), and teriflunomide (N=21), and classified into responders and non-responders to the treatment according to clinical and radiological criteria. In a subgroup of fingolimod responders and non-responders, the percentage of ASC specks in monocytes was determined by flow cytometry, and the levels of IL-1β, IL-18, IL-6, TNFα, and galectin-3 were quantified by ELISA.Results: NLPR3 expression levels were significantly increased in fingolimod non-responders after 3 and 6 months of treatment but remained comparable in responders at all time points. These changes were not observed in non-responders to the other oral therapies tested. ASC speck formation in monocytes following LPS and ATP stimulation was significantly decreased in responders, but increased in non-responders after 6 months of fingolimod treatment. Pro-inflammatory cytokine release from stimulated PBMC was comparable between responders and non-responders, but galectin-3 levels on cell supernatants, as a marker of cell damage, were significantly increased in fingolimod non-responders. Conclusions: The differential effect of fingolimod on ASC speck formation in monocytes between responders and non-responders could be used as response biomarker after 6 months of fingolimod treatment, and suggests that fingolimod may exert their beneficial effects by reducing inflammasome signaling in a subset of MS patients. |
