Interleukin-17 in Chronic Inflammatory Neurological Diseases

Abstract

A critical role for IL-17, a cytokine produced by T helper 17 (Th17) cells, has been indicated in the pathogenesis of chronic inflammatory and autoimmune diseases. A positive effect of blockade of IL-17 secreted by autoreactive T cells has been shown in various inflammatory diseases. Several cytokines, whose production is affected by environmental factors, control Th17 differentiation and its maintenance in tissues during chronic inflammation. The roles of IL-17 in the pathogenesis of chronic neuroinflammatory conditions, multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), Alzheimer's disease, and ischemic brain injury are reviewed here. The role of environmental stimuli in Th17 differentiation is also summarized, highlighting the role of viral infection in the regulation of pathogenic T helper cells in EAE.

Keywords: Alzheimer's disease; EAE; IL-17; Th17; ischemic brain injury.

Figure 1

IL-17 in Inflammatory Diseases of the Central Nervous System. Infection in the periphery (viral infections) activates innate immunity (monocytes/macrophages and NK cells) and induces a proinflammatory environment that changes the phenotype of antigen-presenting cells, which differentiate into inflammatory APCs that produce inflammatory cytokines IL-1, IL-6, IL-12, and IL-23. These APCs induce bystander activation of autoreactive T cells and their differentiation toward encephalitogenic T cells (IFN-γ, IL-17, TNF-α, Tbet, RORγt, CXCR3, and CCR6 positive) capable of entering the CNS, where after reactivation in contact with antigens presented by local tissue APCs, they proliferate and produce cytokines (IL-17, GM-CSF) that contribute to BBB disruption and recruitment of other immune cells into the CNS, finally inducing myelin damage (Multiple sclerosis). Peripheral infections can compromise the BBB and lead to an influx of IL-17-producing cells into the CNS. IL-17 can induce damage to neurons by direct cytotoxic effects or by recruitment of neutrophils and induction of inflammation, leading to deposition of amyloid fibrils and plaque formation (Alzheimer's disease). Also, the opposite order of events is possible, where microglia phagocytize amyloid fibrils and induce differentiation of T cells toward IL-17-producing cells, and the released IL-17 damages the BBB, recruits neutrophils, and induces inflammation and neuron damage, which exacerbates amyloid deposition (Alzheimer's disease). CNS tissue damaged by ischemia releases damage-associated molecular patterns (HMGB1) that stimulate microglia to release inflammatory mediators TNF-α, IL-1β, IL-6, and IL-17, which enhance inflammation and tissue damage. Activated microglia also can induce Th17 development. IL-17 released by innate immune cells or Th17 cells can enhance BBB damage, recruit immune cells, and enhance inflammation, inducing direct neuronal damage (postischemic inflammation).