IL-11 induces NLRP3 inflammasome activation in monocytes and inflammatory cell migration to the central nervous system.
Proceedings of the National Academy of Sciences of the United States of America(2023)
摘要
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 and . All CD4 cell subsets had increased expression of 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, , and migratory genes () 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.
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关键词
nlrp3 inflammasome activation,inflammatory cell migration,monocytes
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