IL-11 induces NLRP3 inflammasome activation in monocytes and inflammatory cell migration to the central nervous system

Abstract

The objective of this study is to examine IL - 11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL -11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL -11+ monocytes, IL -11+ and IL -11R+ CD4+ lymphocytes, and IL -11R+ neu-trophils in comparison to matched healthy controls. IL -11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL -11 in -vitro stimulation, examined using single -cell RNA sequencing, revealed the highest number of differen-tially expressed genes in classical monocytes, including up-regulated NFKB1, NLRP3, and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL -11R+ -sorted cells from the CSF, classical and intermediate monocytes significantly up-regulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with & alpha;IL- 11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates, and demyelination. & alpha;IL-11 mAb treatment decreased the numbers of NF & kappa;Bp65+, NLRP3+, and IL -1(3+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL- 11R signaling in monocytes represents a therapeutic target in RRMS.