The innate immune system in demyelinating disease

Abstract

Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, γδ T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2012 John Wiley & Sons A/S.

Figures

Fig. 1. Mouse models of demyelinating diseases

The demyelinating diseases multiple sclerosis (MS), neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM), are represented as circles, with the corresponding mouse models. MS is further subdivided into a histogram representing the different stages of MS, a decade after initial diagnosis: primary progressive (PP), relapsing remitting (RR), and secondary progressive (SP). Data adapted from (5, 10, 223). aBiozzi mice develop a different EAE pattern depending on the peptide used for disease induction. bC57Bl/6 MOG-induced EAE is a monophasic disease that can be regarded as a single attack (ADEM) or represent the first attack in RRMS.

Fig. 2. Role of innate cells in modulating CNS demyelinating disease

An innate cell in the CNS may recruit peripheral cells and affect the integrity of the BBB. It can activate CD4+ T cells and induce a pro-demyelinating effector phenotype (Th1, Th17, or Th9) or a regulatory T-cell phenotype (Foxp3+ Treg, and Tr1); or terminate the CD4+ response by inducing apoptosis. The innate cell can also activate and modulate other adaptive cells such as CD8+ cytotoxic T cells, B cells, or other innate cells (either peripheral or central). The innate cell can directly affect the demyelinating and remyelinating processes by breaking down myelin, clearing (phagocytosis) myelin, debris, and dead cells, and by affecting oligodendrocyte and neuronal viability. The innate cell can also affect NG2/OPC (oligodendrocyte precursor cell) maturation into oligodendrocytes, and their migration to the lesion site, as well as modulating axonal growth.

Fig. 3. Astrocyte modulation of T cells

Astrocytes recruit T cells into the CNS by chemokine production, by expression of adhesion molecules (e.g. ICAM-1, VCAM-1), and by regulating passage through the BBB [by cytokine and MMP production or MMP inhibition (TIMP-1)]. Astrocytes induce T-cell activation via antigen presentation, cytokine production [TGF, IL-6, IL-23, IL-10, and osteopontin (OPN)], and use other signaling molecules to modulate the T-cell response [e.g. CD24, galectin-9 (Gal-9) and PD-L1]. Astrocytes may also prevent or terminate the T-cell response by inducing T-cell apoptosis, expression of FAS-L, or by other mediators such as nitric oxide, astrocyte-derived immune suppressor factor (AdIF), and osteonectin.