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+ neutrophils 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 differentially 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 αIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates, and demyelination. αIL-11 mAb treatment decreased the numbers of NFκBp65+, NLRP3+, and IL-1β+ 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.
Seyedsadr, Maryamsadat; Wang, Yan; Elzoheiry, Manal; Shree Gopal, Sowmya; Jang, Soohwa; Duran, Gayel; Chervoneva, Inna; Kasimoglu, Ezgi; Wrobel, John A.; Hwang, Daniel; Garifallou, James; Zhang, Xin; Khan, Tabish H.; Lorenz, Ulrike; Su, Maureen; Ting, Jenny P.; Broux, Bieke; Rostami, A M; Miskin, Dhanashri; and Markovic-Plese, Silva, "IL-11 Induces NLRP3 Inflammasome Activation in Monocytes and Inflammatory Cell Migration to the Central Nervous System" (2023). Department of Neurology Faculty Papers. Paper 324.
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