2024 American Academy of Neurology Abstract Website

Objective:

To study the role of IL-11-mediated NLRP3 inflammasome activation in inflammatory cell migration to the CNS and neurotoxicity in patients with relapsing remitting multiple sclerosis (RRMS).

Background:

IL-11⁺ cells were enriched in the CSF and in active brain lesions in RRMS patients. Using scRNAseq, we characterized the IL-11-induced transcriptome changes in immune cells from MS patients. Following reports on the NLRP3 expression in neurons and caspase 1-induced pyroptotic neuronal cell death, which is reversed by NLRP3 gene KO or silencing, and by its inhibitor MCC950, we examined the molecular mechanisms of neurotoxicity of the MS CSF, and of IL-11 in human inducible pluripotent stem cell (iPS)-derived neurons.

Design/Methods:

Monocytes and CD4⁺ cells from PBMCs of MS patients were used for validation of scRNAseq gene and protein expression. Anti-IL11 mAb was used in RREAE to determine its therapeutic potential. iPS-derived human neuronal cultures were used to detect neurotoxic effect of MS CSF and IL-11. In order to test if the effect was mediated via NLRP3 inflammasome activation, the the cultures were treated with NLRP3 inflammasome inhibitor MCC950.

Results:

In IL-11R⁺-sorted cells from CSF, classical and intermediate monocytes significantly upregulated the expression of multiple NLRP3 inflammasome-related genes. Therapeutic targeting of this pathway with aIL-11 mAb decreased the numbers of NFkBp65⁺, NLRP3⁺ and IL-1b⁺ monocytes in the CNS of mice with EAE.

We report that IL-11 induced neuronal death in dose-dependent manner in human cortical neuronal cultures. The effect is inhibited by NLRP3 inhibitor MCC950, supporting IL-11-NLRP3 inflammasome induced neuronal death. Importantly, CSF samples from MS patients induced a similar degree of neuronal cell death and the studies of inflammasome-dependent signaling pathways involved in neuronal death are in progress.

Conclusions:

IL-11 induces NLRP3 inflammasome priming, whose therapeutic targeting may be prevent inflammatory cell migration to the CNS and the neuronal loss in RRMS.