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Autism-Like Symptoms in Mice: the link to the Th17–IL-17–IL-17R System and an Altered Brain Development

Autism-Like Symptoms in Mice

Autism-Like Symptoms in Mice – the link to the Th17–IL-17–IL-17R System

A new report published in Science indicates that the key pro-inflammatory cytokine interleukin (IL)-17a may interfere with the normal brain development in a mouse model of autism, causing disorganized cortical cytoarchitecture and autism-like symptoms.

Previous research also suggests that viral infection of mothers during pregnancy may contribute to a higher incidence of ASD in the offspring (Atladóttir et al., 2010; Lee et al., 2015). Several studies have suggested this link.

Thus, in the rodent maternal immune activation (MIA) model of this phenomenon, offspring from pregnant mice infected with virus or injected intraperitoneally with synthetic double-stranded RNA (dsRNA) [poly(I:C)], a mimic of viral infection, exhibit behavioral symptoms reminiscent of ASD: social deficits, abnormal communication, and repetitive behaviors – and autism-like symptoms.

IL-17 is a highly pathogenic pro-inflammatory cytokine, considered a major player in several autoimmune/inflammatory diseases, whereas altered cytokine profiles and increased serum IL-17 levels.

TH17 cells and their cytokine mediators have been suggested to have a role in ASD. For example, elevated levels of interleukin-17a (IL-17a), the predominant TH17 cytokine, have been detected in the serum of a subset of autistic children. A genome-wide copy number variant (CNV) analysis identified IL17A as one of many genes enriched in autistic patients. Similarly, in the MIA mouse model, CD4+ T lymphocytes from affected offspring produced higher levels of IL-17a upon in vitro activation.

However, no study has yet correlated the Th17 cell responses in pregnant women with the risk of ASD development in the offspring.

A disease model in rodents, referred to as ‘maternal immune activation’ (MIA) has been often used to study viral and immune activation in the mother during pregnancy, and the link to autism-like behaviors in the offspring. In this model pregnant mice are injected with the synthetic double-stranded RNA, poly(I:C), to mimic a viral infection.

Previous data indicate that in the MIA model, with autism-like symptoms, the immune cells, and particularly the CD4+ T lymphocytes from the affected offspring, produce high amounts of IL-6 and IL-17 upon in vitro stimulation. In addition, earlier studies showed that MIA induces in the offspring behavioral impairments similar to those that are observed in autistic children. This includes reduced social interaction, abnormal communication and stereotyped/repetitive behaviour.

In the Science report, Gloria Choi and colleagues from the Massachusetts Institute of Technology, Cambridge, MA, and the New York University School of Medicine, NY used the MIA model to study if the highly pathogenic IL-17-IL-17R pathway may contribute to abnormal fetal brain development and autism-like behavioral phenotypes.

The authors found that in mothers, T helper (Th)17 cells and their effector cytokine IL-17 are required before the MIA-induced behavioral abnormalities (and autism-like symptoms) are observed in the offspring.

They report that pregnant mothers, injected with poly(I:C), had a strong induction of serum IL-6 and IL-17 cytokine levels (of note, IL-6 is a key factor for Th17 cell differentiation). In addition, they found that the expression of the IL-17 receptor subunit A (IL-17Ra) was strongly augmented in the fetal brain upon induction of MIA.

Importantly, the maternal IL-17a was able to induce abnormal cortical development in offspring, related to patches of disorganized cortical cytoarchitecture. Moreover, the maternal IL-17a promoted ASD-like behavioral abnormalities in the offspring.

Corroborating this data, in the study of Choi et al., the injection of pregnant mothers with antibodies against IL-17 supressed the increased IL-17Ra expression in fetus brain and prevented the development of ASD-like behavioral abnormalities.

Thus, these results suggest that an immunological activation during pregnancy may have important long-term outcomes in the offspring. This study finds that the Th17-IL-17-IL-17R pathway is able to affect neuronal development, and, identifies a specific maternal immune cell population that exerts a direct role in inducing ASD-like phenotypes by acting on the developing fetal brain.

Of note, the authors discuss that some of the IL-17 effects might be related to the structural similarities detected between the IL-17 family cytokines and neurotrophins such as the nerve growth factor.

Also of interest is a recent study, published in Cell, indicating that Th17 cells are able to induce tertiary lymphoid tissues (TLTs) within the brain meninges, which are linked to the formation of an immune-competent stromal cell niche in the meninges and local demyelination.

Source: Science, 2016, 351:933-9. doi: 10.1126/science.aad0314. Epub 2016 Jan 28.
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