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Maternal IL-17A in autism - PubMed

Review

Maternal IL-17A in autism

Helen Wong et al. Exp Neurol. 2018 Jan.

Abstract

Although autism spectrum disorder (ASD) has a strong genetic basis, its etiology is complex, with several genetic factors likely to be involved as well as environmental factors. Immune dysregulation has gained significant attention as a causal mechanism in ASD pathogenesis. ASD has been associated with immune abnormalities in the brain and periphery, including inflammatory disorders and autoimmunity in not only the affected individuals but also their mothers. Prenatal exposure to maternal immune activation (MIA) has been implicated as an environmental risk factor for ASD. In support of this notion, animal models have shown that MIA results in offspring with behavioral, neurological, and immunological abnormalities similar to those observed in ASD. This raises the question of how MIA exposure can lead to ASD in susceptible individuals. Recent evidence points to a potential inflammation pathway linking MIA-associated ASD with the activity of T helper 17 (Th17) lymphocytes and their effector cytokine interleukin-17A (IL-17A). IL-17A has been implicated from human studies and elevated IL-17A levels in the blood have been found to correlate with phenotypic severity in a subset of ASD individuals. In MIA model mice, elevated IL-17A levels also have been observed. Additionally, antibody blockade to inhibit IL-17A signaling was found to prevent ASD-like behaviors in offspring exposed to MIA. Therefore, IL-17A dysregulation may play a causal role in the development of ASD. The source of increased IL-17A in the MIA mouse model was attributed to maternal Th17 cells because genetic removal of the transcription factor RORγt to selectively inhibit Th17 differentiation in pregnant mice was able to prevent ASD-like behaviors in the offspring. Similar to ASD individuals, the MIA-exposed offspring also displayed cortical dysplasia which could be prevented by inhibition of IL-17A signaling in pregnant mice. This finding reveals one possible cellular mechanism through which ASD-related cognitive and behavioral deficits may emerge following maternal inflammation. IL-17A can exert strong effects on cell survival and differentiation and the activity of signal transduction cascades, which can have important consequences during cortical development on neural function. This review examines IL-17A signaling pathways in the context of both immunity and neural function that may contribute to the development of ASD associated with MIA.

Keywords: ASD; Autism; Cytokine; IL-17 receptor; Il-17; Il-6; Maternal inflammation; Mia; Mouse behavior; RORγt; Th17.

Copyright © 2017 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1

IL-17A and immunity: Infection causes increased expression and secretion of the proinflammatory cytokine interleukin-6 (IL-6). In the presence of the cytokine transforming growth factor β (TGFβ), IL-6 can stimulate the differentiation of naïve CD4+ lymphocytes into T helper 17 (Th17) cells. A key downstream effector of IL-6 involved in Th17 differentiation is the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt). RORγt promotes transcription of the pro-inflammatory cytokine IL-17A. IL-17A signaling plays a protective role in adaptive immunity. Dysregulation of Th17 cells and IL-17A production are associated with autoimmune diseases and inflammatory disorders. IL-17A and ASD: In the case of maternal immune activation (MIA), IL-6 is induced and stimulates the differentiation of Th17 cells in the mother, leading to increased IL-17A secretion. IL-17A in turn crosses the placental barrier or is induced in the fetus, where it can act on cells expressing the receptor IL-17RA in the developing nervous system. Stimulation of IL-17RA can activate several intracellular signaling pathways mediated by Act1, such as NF-κB, ERK, p38 MAPK, and TRAF2/5. Consequently, various developmental processes can be altered, including neural stem cell (NSC) proliferation, gliogenesis, microglial function, blood-brain barrier activity, and neuronal connectivity. In these ways, inappropriate Th17 cell and IL-17A activity may adversely impact prenatal development, resulting in cortical dysplasia and the manifestation of behaviors associated with ASD in the offspring (Choi et al. 2016).

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