Current ?disease-modifying drugs? for MS have changed the course of disease with decrease in relapse and possible slowing of the progression. however, many patients eventually experience relapses and/or disease progression. There is thus a clearly unmet need for developing safer and more effective MS therapies. IL-37, a member of the IL-1 family of cytokines, has been recently recognized as a novel immunoregulatory cytokine. Importantly, IL-37 exerts its function through a ?dual-effect? property, i.e., both as a secreted cytokine that will act through its receptor IL-37R (SIGIRR and IL-18Ra) and as a transcription factor, and this distinct property may make IL-37 a more powerful immunomodulator than most conventional cytokines for clinical application. Based on the literature and our preliminary observations, we hypothesize that IL-37 is a key regulator of inflammation in CNS autoimmunity through induction of amphiregulin, a tissue-repair associated cytokine with immunomodulatory properties. To test this hypothesis, we propose the following specific aims: (1) To define IL-37R expression and IL-37 responsiveness in immune cells of MS patients. We will first identify the source(s) of IL-37 and compare IL-37R expression and responsiveness to IL-37 in immune cells of MS patients vs. healthy controls. We will also test our hypothesis that IL-37 treatment will block proinflammatory monocyte- or Th1/Th17 cell-induced demyelination, using a novel organotypic slice culture system of adult human brain tissue. (2) To determine the effect of IL-37 on CNS resident cells during autoimmune neuroinflammation. We will first test the effect of IL-37 on microglia, astrocytes and oligodendrocytes of murine and human origin. We will then determine the expression of IL-37R in CNS resident cells from patients with MS. Finally, we will test if upregulation of the IL-37R (TIR8 subunit) suppresses neuroinflammation. 3) To investigate the induction of the amphiregulin pathway as a possible mechanism of IL-37 action. This will be tested in amphiregulin conditional knockout EAE mice and monocytes and T/B cells of healthy subjects and. MS patients. Information gained from these studies could result in a better understanding of pathogenic mechanisms of MS and in the development of new strategies for regulating the immune response in order to stop the progression of this disease, and likely other autoimmune diseases.
In this project we will test the effect and mechanism of a newly defined immunomodulatory cytokine, interleukin 37, on immune cells and brain resident cells and tissues of mice and patients with multiple sclerosis. These studies should provide an insight into the potential use of interleukin 37 as a novel and more effective therapy for multiple sclerosis and likely other human autoimmune diseases.
