New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Abstract

Multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis, are neuroinflammatory diseases driven by autoreactive pathogenic T_H cells that elicit demyelination and axonal damage. How T_H cells acquire pathogenicity and communicate with myeloid cells and cells of the CNS remain unclear. IL-1β is recognized to play an important role in experimental autoimmune encephalomyelitis (EAE) and perhaps MS. Clinical EAE is significantly attenuated in IL-1R-deficient and IL-1β-deficient mice, and IL-1β is found in the blood, cerebrospinal fluid, and CNS lesions of MS patients. In this article, we focus on new reports that elucidate the cellular sources of IL-1β and its actions during EAE, in both lymphoid tissues and within the CNS. Several immune cell types serve as critical producers of IL-1β during EAE, with this cytokine inducing response in both hematopoietic and nonhematopoietic cells. These findings from the EAE model should inspire efforts toward investigating the therapeutic potential of IL-1 blockade in MS.

Figure 1. The Cellular Sources of IL-1β and Its Target Cells during EAE

In the EAE model in C57BL/6 mice, animals are immunized with MOG_35-55/CFA subcutaneously and treated with pertussis toxin (PTX) systemically. Five to eight days after immunization, IL-1β is primarily produced by CD11b⁺Ly6C^mid-hiMHC II^lo-hi monocyte-derived DC/macrophages (moDCs/Macs) in the peripheral DLNs. Activated CD4⁺ T cells have also been recently appreciated to be cellular sources of IL-1β. Although T cell-derived IL-1β is dispensable for CD4⁺ T cell priming in DLNs before disease onset, IL-1β derived from pathogenic T cells may be important to initiate inflammation within the CNS. IL-1β production from meningeal mast cells has also shown to be critical for EAE susceptibility and CD4⁺ T cell encephalitogenicity. Neutrophils and moDC/Macs also produce IL-1β in the CNS. Multiple cell types respond to IL-1β during EAE. IL-1β enhances Bhlhe40 expression and GM-CSF production by CD4⁺ T cells in both the DLN and the CNS and promotes T cell pathogenicity. Most of the myeloid cell subsets in the DLNs express IL-1R but whether they respond to IL-1β to facilitate disease progression is unclear. In the CNS, IL-1β can stimulate astrocytes to secrete chemokines which may recruit and activate leukocytes. Action of IL-1β on CNS endothelial cells facilitates cytokine production and neutrophil adhesion. Small arrows indicate cytokine or chemokine production. Large red and blue arrows indicate the actions of IL-1β and GM-CSF, respectively.