Th17 cells and inflammation in neurological disorders: Possible mechanisms of action

Abstract

Neurological disorders (NDs) are one of the leading causes of global death. A sustained neuroinflammatory response has been reported to be associated with the pathogenesis of multiple NDs, including Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and major depressive disorder (MDD). Accumulating evidence shows that the recruitment of abundant lymphocytes in the central nervous system may contribute to promoting the development and progress of inflammation in neurological disorders. As one subset of T lymphocytes, CD4⁺ T cells have a critical impact on the inflammation of neurological disorders. T helper (Th) 17 is one of the most studied CD4⁺ Th subpopulations that produces cytokines (e.g., IL-17A, IL-23, IL-21, IL-6, and IFN-γ), leading to the abnormal neuroinflammatory response including the excessive activation of microglia and the recruitment of other immune cell types. All these factors are involved in several neurological disorders. However, the possible mechanisms of Th17 cells and their associated cytokines in the immunopathology of the abovementioned neurological disorders have not been clarified completely. This review will summarize the mechanisms by which encephalitogenic inflammatory Th17 cells and their related cytokines strongly contribute to chronic neuroinflammation, thus perpetuating neurodegenerative processes in NDs. Finally, the potential therapeutic prospects of Th17 cells and their cytokines in NDs will also be discussed.

Keywords: IL-17A; Th17 cells; immune system; microglia; neuroinflammation; neurological disorders.

Figure 1

Differentiation of Th17 cells and its secretion of inflammatory cytokines. Under the microenvironment of pro-inflammatory cytokines (IL-6, IL-21, and/or TGF-β), naive CD4⁺ T precursors can be induced to differentiate into Th17 cells, which have crucial roles in the immunopathogenesis of neurological disorders. Nonetheless, IFN-γ (a Th1 cell-related cytokine) and IL-4 (a Th2 cell-related cytokine) can inhibit the differentiation of Th17 cells from naive CD4⁺ T cells as long as Th17 cells have not been fully developed. These primary differentiated Th17 cells will express specific transcription factors, such as RORγt and STAT3. IL-21 is produced by Th17 cells in an autocrine manner and other cells then promote Th17 cell proliferation and differentiation (expansion stage). IL-23 promotes the terminal differentiation, development, and survival of expanded Th17 cells in their final stable state. IL, interleukin; TGF-β, transforming growth factor-β; IFN-γ, interferon-γ; STAT, signal transducer and activator of transcription.

Figure 2

Th17 cells and their cytokines in neurological disorders: possible mechanisms of action. Multiple environmental factors (peripheral inflammation, enhanced oxidative stress, gut–brain axis) induce a pro-inflammatory microenvironment that modifies the CD4⁺ T-cell phenotype and then differentiates into encephalitogenic Th17 cells, producing inflammatory cytokines (IL-17A, IL-6, IL-21, IFN-γ, GM-CSF, and IL-23). These Th17 cells are capable of entering the CNS. They proliferate and produce cytokines that are conducive to BBB disruption and recruitment of other immune cells (lymphocytes, macrophages, and neutrophil cells) into the CNS, ultimately leading to myelin damage (multiple sclerosis). Th17 cells and their cytokines can cause neuronal damage through direct cytotoxic effects or through recruitment of immune cells and induction of neuroinflammation, resulting in deposition of Aβ fibrils or the aggregation of αSyn (Alzheimer’s disease/Parkinson’s disease). Additionally, Th17 cells can activate the microglia and phagocytose amyloid fibrils, but neuroinflammation will induce microglia damage, thereby exacerbating amyloid β deposition or αSyn aggregation (Alzheimer’s disease/Parkinson’s disease). GM-CSF, granulocyte monocyte-colony stimulating factor; Aβ, amyloid β.