The role of interferon-β in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis - in the perspective of inflammasomes

Abstract

Inflammasomes in innate immune cells mediate the induction of inflammation by sensing microbes and pathogen-associated/damage-associated molecular patterns. Inflammasomes are also known to be involved in the development of some human and animal autoimmune diseases. The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is currently the most fully characterized inflammasome, although a limited number of studies have demonstrated its role in demyelinating autoimmune diseases in the central nervous system of humans and animals. Currently, the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is known to be induced by the NLRP3 inflammasome through enhanced recruitment of inflammatory immune cells in the central nervous system. On the other hand, interferon-β (IFNβ), a first-line drug to treat MS, inhibits NLRP3 inflammasome activation, and ameliorates EAE. The NLRP3 inflammasome is indeed a factor capable of inducing EAE, but it is dispensable when EAE is induced by aggressive disease induction regimens. In such NLRP3 inflammasome-independent EAE, IFN-β treatment is generally not effective. This might therefore be one mechanism that leads to occasional failures of IFN-β treatment in EAE, and possibly, in MS as well. In the current review, we discuss inflammasomes and autoimmunity; in particular, the impact of the NLRP3 inflammasome on MS/EAE, and on IFN-β therapy.

Figure 1

Schematic diagram: Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome induces experimental autoimmune encephalomyelitis (EAE) development by cell recruitment to the central nervous system (CNS), but interferon-β (IFN-β) inhibits NLRP3 inflammasome activity. Active NLRP3 inflammasome in antigen-presenting cells [APCs; macrophages (Mϕ) and dendritic cells (DC)] processes maturation of IL-1β and IL-18, which are detected by CD4⁺ and APCs, in paracrine and autocrine fashions, respectively. The cytokines induce expression of genes encoding migration-related proteins in T cells and APCs in the peripheral lymphoid organs, resulting in enhancement of cell migration into the CNS; and this causes development of EAE. On the other hand, IFN-β inhibits activation of the NLRP3 inflammasome in APCs through IFN-I receptor (IFNAR) signalling induction of Suppressor Of Cytokine Signalling-1 (SOCS1). SOCS1 down-regulates Rac1-GTP (active Rac1) and reactive oxygen species (ROS) generation, resulting in inhibition of NLRP3 inflammasome activation. DAMP, damage-associated molecular patterns; OPN, osteopontin; PAMP, pathogen-associated molecular patterns.

Figure 2

Two subtypes of experimental autoimmune encephalomyelitis (EAE). EAE induced by conventional disease induction regimens or adoptive transfer of activated T cells is accompanied with active Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is a target of interferon-β (IFN-β), and expression of interleukin-1β (IL-1β) and IL-18. IFN-β is effective in such EAE. In contrast, aggressive disease induction regimens can trigger NLRP3 inflammasome-independent EAE, which is not ameliorated by IFN-β treatment. It is not clear what mediates EAE progression, instead of the NLRP3 inflammasome. The two subtypes are not mutually exclusive.