IL-11-induced NLRP3 inflammasome activation mediates pyroptotic cell death in human neurons 2260831

Abstract

Abstract Introduction IL-11, a member of the IL-6 cytokine family, is significantly increased in the serum and cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RRMS), and serum IL-11 levels correlate with clinical relapses. This study examined the neurotoxic effect of IL-11 and its role in the NLRP3 inflammasome activation in human neurons. S1PR1 signaling promotes NLRP3/IL-1b expression. We propose that inhibiting IL-11-induced NLRP3 inflammasome activation in neurons using anti-IL-11 mAb, NLRP3 inhibitor MCC950, and an S1PR inhibitor Ozanimod, may provide a neuroprotective effect. Methods Human inducible pluripotent stem cell (iPSC)-derived neurons were labeled with DRAQ7 dye, which incorporates in the nuclei of dead cells. We examined the neurotoxicity of IL-11 (100 and 200 ng/ml), CSF from 10 untreated RRMS patients (1:25 dilution) and 10 control donors in the absence or presence of anti-IL11 mAb, MCC950 and Ozanimod. Dead cells were scored by visualization of DRAQ7-positive neurons. Results We identified the expression of IL-11R, NLRP3 and caspase-1 in iPSC-derived human neurons by immunofluorescent (IF) staining. IL-11 induced neuronal death in a dose-dependent manner. The effect was inhibited by the selective NLRP3 inhibitor MCC950, which blocks the inflammasome activation, indicating that IL-11-NLRP3 inflammasome activation mediates the neuronal cell death. CSF samples from 10 RRMS patients induced a similar degree of neuronal cell death (57.8%), which was significantly higher in comparison to the CSF from matched control donors or PBS (15.3%). The neurotoxic effect of the MS CSF was detected at day 7, and it was inhibited by human anti-IL-11 mAb (12.8%), MCC950 (17.2%) and Ozanimod (11.3%). Conclusion IL-11 within the CSF induces neuronal cell death, which is mediated via NLRP3 inflammasome-induced pyroptosis. Anti-IL11 mAb, MCC950, and Ozanimod demonstrated a neuroprotective effect. Funding Source NIH, R01 Topic Categories Neuroimmunology (NEUR)