Increased NLRP3 Inflammasome Activation and Pyroptosis in Patients With Multiple Sclerosis With Fingolimod Treatment Failure
Malhotra, Sunny (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Hurtado-Navarro, Laura (Hospital Universitari Vall d'Hebron)
Pappolla, Agustin (Hospital Universitari Vall d'Hebron)
Villar, Luisa M. (Hospital Universitari Vall d'Hebron)
Río, Jordi (Hospital Universitari Vall d'Hebron)
Montalban, Xavier (Hospital Universitari Vall d'Hebron)
Pelegrín, Pablo (Hospital Universitari Vall d'Hebron)
Comabella, Manuel (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Date:	2023
Abstract:	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 patients with MS. 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 patients with MS treated with fingolimod (N = 23), dimethyl fumarate (N = 21), and teriflunomide (N = 21) and classified into responders and nonresponders to the treatment according to clinical and radiologic criteria. In a subgroup of fingolimod responders and nonresponders, the percentage of monocytes with an oligomer of ASC was determined by flow cytometry, and the levels of interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor (TNF)α, and galectin-3 were quantified by ELISA. NLPR3 expression levels were significantly increased in fingolimod nonresponders after 3 (p = 0. 03) and 6 months (p = 0. 008) of treatment compared with the baseline but remained similar in responders at all time points. These changes were not observed in nonresponders to the other oral therapies tested. The formation of an oligomer of ASC in monocytes after lipopolysaccharide and adenosine 5'-triphosphate stimulation was significantly decreased in responders (p = 0. 006) but increased in nonresponders (p = 0. 0003) after 6 months of fingolimod treatment compared with the baseline. Proinflammatory cytokine release from stimulated peripheral blood mononuclear cells was comparable between responders and nonresponders, but galectin-3 levels on cell supernatants, as a marker of cell damage, were significantly increased in fingolimod nonresponders (p = 0. 02). The differential effect of fingolimod on the formation of an inflammasome-triggered ASC oligomer in monocytes between responders and nonresponders could be used as a 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 patients with MS.
Grants:	Agencia Estatal de Investigación PID2020-116709RB-I00 Instituto de Salud Carlos III DTS21/00080
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Neurology® neuroimmunology & neuroinflammation, Vol. 10 (march 2023) , ISSN 2332-7812

DOI: 10.1212/NXI.0000000000200100
PMID: 36973075

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