IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production

Abstract

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R 2/2 mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R 2/2 mice correlates with increased numbers of GM-CSF + CD4 + T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R 2/2 mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4 + T cells through the modulation of DCs.

Engineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis

“…For example, the INs could be used to develop a further understanding of T-cell subsets in inflamed tissue in EAE by taking longitudinal biopsies throughout the disease course. Certainly, T-cells are responsible for disease initiation, but our understanding continues to evolve 35 , 36 . Ultimately, the IN assesses peripheral immune events, which the data demonstrates are reflective of immunopathological events occurring in the CNS.…”

Crosstalk between the Producers and Immune Targets of IL-9

“…IL-9-activated BMDCs did not alter the frequency of Th17 and Tregs in vitro ( 12 70 ). In contrast, in an EAE model, splenic DC from Il9 −/− mice were found to express more IL-1β, IL-6, IL-23A and less IL-27, and they induced naïve CD4 + T cells to produce more IFN-γ compared with control mice ( 10 ).…”

“…IL-9 has been reported to induce the development of a number of autoimmune diseases such as inflammatory bowel diseases (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) ( 7 8 9 ). However, there are also somewhat conflicting reports in which IL-9 was found to suppress experimental autoimmune encephalomyelitis (EAE) in mice ( 10 11 ). IL-9 contributes to the pathophysiology of allergic diseases like food allergy, dermatitis or asthma through its autocrine or paracrine effect on T cells, B cells, innate lymphoid cells, mast cells, eosinophils, and neutrophils ( 12 13 14 15 16 17 ).…”

Comprehensive Analysis of the Immune and Stromal Compartments of the CNS in EAE Mice Reveal Pathways by Which Chloroquine Suppresses Neuroinflammation

“…To induce and evaluate EAE, we followed previously described protocols [ 33 , 34 ]. Mice were subcutaneously immunized with 200 µg of MOG 35-55 peptide (Genscript) and equal volume of Complete Freund’s adjuvant supplemented with 10 mg/mL of heat-killed Mycobacterium tuberculosis H37Ra.…”

“…Mononuclear cells from the CNS of EAE mice were isolated by Percol gradient centrifugation following published reports [ 32 , 33 , 34 ]. In brief, euthanized mice were perfused with ice-cold PBS and the CNS tissue was collected and incubated with 700 µg/mL Liberase TL (Sigma-Aldrich, St. Louis, MO, USA) at 37 °C for 30 min.…”