IL-11 induces monocyte inflammasome activation and migration to the CNS in IL-11R+ cells in relapsing remitting multiple sclerosis (RRMS)

Abstract

Abstract Objective To examine the effect of IL-11 on the transcriptome changes in the blood and cerebrospinal fluid (CSF)-derived cells from RRMS patients. Methods IL-11+ expressing cells in PBMC or CSF were characterized by flow cytometry (n=14 and 9 respectively). Single cell RNA sequencing (scRNAseq) was performed for IL-11R+ sorted peripheral blood-derived cells following IL-11 stimulation (1 hour) (n=3 RRMS patients) or CSF and blood samples (n=2 RRMS patients). The animal model of RRMS (RREAE) was used to test the therapeutic effect of anti-IL11 mAb. Results RRMS patients have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes and IL-11R+ neutrophils in comparison to matched HCs. IL-11 expressing monocytes, CD4+ lymphocytes and neutrophils accumulate in the CSF of RRMS patients in comparison to paired blood samples. scRNAseq for IL-11R+ sorted cells following IL-11 stimulation, revealed the highest number of differentially expressed genes (DEGs) in classical monocytes with upregulation of NFKB1, NLRP3 and IL1B genes involved in the inflammasome activation. All CD4+ cell subsets had an increased expression of S100A8/9 genes involved in the inflammasome activation. ScRNAseq for IL-11R+-sorted cells from the CSF revealed that classical and intermediate monocytes upregulate multiple complement, inflammasome-induced (IL-18), and migratory genes. aIL-11 mAb in RREAE decreased clinical scores, CNS inflammatory infiltrates, demyelination, IL-11+ CD4+ cells and monocytes, and numbers of NFkBp65+, NLRP3+ and IL-1b+ monocytes within the CNS. Conclusion IL-11/IL-11R signaling in monocytes represents a therapeutic target in early RRMS. The study was supported by NIH 1R01AI131238-01A1 and PA Cure SAP4100083100 grant.