The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring.

Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt)-dependent effector T lymphocytes [for example, T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes.

Choi GB ，Yim YS ，Wong H ，Kim S ，Kim H ，Kim SV ，Hoeffer CA ，Littman DR ，Huh JR ... -  《-》

Neuroimmunology: IL-17A mediates a path to autism.

Kugelberg E 《-》

IMMUNOLOGY. Maternal TH17 cells take a toll on baby's brain.

Estes ML ，McAllister AK 《-》

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.

Kim S ，Kim H ，Yim YS ，Ha S ，Atarashi K ，Tan TG ，Longman RS ，Honda K ，Littman DR ，Choi GB ，Huh JR ... -  《-》

Maternal IL-17A in autism.

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.

Wong H ，Hoeffer C 《-》