NLR Family Pyrin Containing 3 (NLRP3) Inflammasome Activation Mediates Human Inducible Pluripotent Stem Cell (iPSC)-derived Neuronal Death 9345

Abstract Description Ozanimod, an FDA-approved first-line treatment for relapsing-remitting multiple sclerosis (RRMS), crosses the blood-brain barrier and may offer neuroprotective effects. We propose that this sphingosine-1 phosphate (S1P) inhibitor exerts neuroprotective effect by inhibiting NLRP3 inflammasome activation. Blood samples from 16 RRMS patients were analyzed at baseline and at 1, 3, 6, and 12 months after starting Ozanimod treatment. A significant reduction in serum IL-18 level was observed after 6 months of treatment. Flow cytometry study of nine gated cell subsets (CD3 + [CD4+, CD8+, gdTCR+ T-cells], CD56+ NK-cells, CD19+ B-cells, CD14+ monocytes, CD68+ macrophages, BDCA1/3+ myeloid (m)DCs and BDCA2/4+ plasmacytoid (p)DCs) revealed increased percentages of nerve growth factor (NGF)-secreting pDCs and CD4+ T cells, as well as brain-derived neurotrophic factor (BDNF)-secreting CD14+ monocytes. In-vitro studies using human iPSC-derived cortical neurons revealed that Ozanimod reduced IL-11- and RRMS cerebrospinal fluid (CSF)-induced neuronal death. The reduction was comparable to the effect of MCC950, a specific NLRP3 inflammasome inhibitor. Our findings suggest that Ozanimod may provide neuroprotective effect by inhibiting NLRP3 inflammasome activation in RRMS patients. Current studies are further investigating the neuroprotective effects of Ozanimod using additional CSF samples from RRMS patients in neurotoxicity assays and immunofluorescent iPSC neuronal staining. Funding Sources The study was supported by the investigator-initiated study (ISS), sponsored by Bristol Myers-Squibb, Inc. Topic Categories Neuroimmunology (NEUR)