IL-17a promotes sociability in mouse models of neurodevelopmental disorders

Reed, Michael D.; Yim, Yeong Shin; Wimmer, Ralf; Kim, Hyun-Ju; Ryu, Changhyeon; Welch, Gwyneth; Andina, Matias; King, Hunter Oren; Waisman, Ari; Halassa, Michael M.; Huh, Jun R.; Choi, Gloria B.

doi:10.1038/s41586-019-1843-6

“…Although the widespread anecdotal reports of the fever response in a substantial fraction of autistic patients have been corroborated 41,42 , the mechanisms of the "fever effect" in patients with ASD are just beginning to be understood 43 . Fever may activate general cellular stress responses, which involve at least two cellular signaling pathways: the Keap1/Nrf2/ARE cytoprotective pathway and the heat shock/proteasomal pathway that protects against a wide variety of disturbances of cellular functions, and these two pathways are interrelated 44,45 .…”

mentioning

confidence: 99%

Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder

Liu

¹

,

Zimmerman

²

,

Singh

³

et al. 2020

Sci Rep

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Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders with no drugs treating the core symptoms and no validated biomarkers for clinical use. The multi-functional phytochemical sulforaphane affects many of the biochemical abnormalities associated with ASD. We investigated potential molecular markers from three ASD-associated physiological pathways that can be affected by sulforaphane: redox metabolism/oxidative stress; heat shock response; and immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with ASD. We first analyzed the mRNA levels of selected molecular markers in response to sulforaphane ex vivo treatment in PBMCs from healthy donors by real-time quantitative PCR. All of the tested markers showed quantifiability, accuracy and reproducibility. We then compared the expression levels of those markers in PBMCs taken from ASD patients in response to orally-delivered sulforaphane. The mRNA levels of cytoprotective enzymes (NQO1, HO-1, AKR1C1), and heat shock proteins (HSP27 and HSP70), increased. Conversely, mRNA levels of pro-inflammatory markers (IL-6, IL-1β, COX-2 and tnf-α) decreased. Individually none is sufficiently specific or sensitive, but when grouped by function as two panels, these biomarkers show promise for monitoring pharmacodynamic responses to sulforaphane in both healthy and autistic humans, and providing guidance for biomedical interventions. Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders that, in the United States, is currently estimated to affect 1 out of 59 children who are 8 years old 1. Despite decades of research and advances in our knowledge of the etiologies of ASD, treatments and biomarkers for ASD remain limited 2-5. To date, the primary diagnosis of ASD still relies on observational tools that are by nature subjective 3,6. Genetic and metabolic studies may provide additional clues to specific etiologies or treatments, but there are no generally accepted biological markers for commonly affected cellular pathways in ASD 5,6. Studies over the last two decades have implicated that physiological and metabolic abnormalities, such as immune dysregulation/neuro-inflammation, redox imbalance/oxidative stress, mitochondrial dysfunction, environmental toxicant exposures and gut dysbiosis, are important aspects of the pathophysiology of ASD 6. Closer examination of the biological markers of pathways associated with ASD could be informative regarding its

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“…Maternal immune activation (MIA) has been suggested to affect fetal brain development and to cause autism spectrum disorder (ASD) symptoms. Interleukin 17A (IL-17A) is a candidate mediator responsible for MIAinduced ASD pathogenesis [1][2][3][4]. In a commonly used mouse model of MIA, polyinosinic-polycytidylic acid [poly(I:C)], a viral mimic that potently induces inflammation, is administered to pregnant female mice [5,6].…”

Section: Introductionmentioning

confidence: 99%

Intraventricular IL-17A administration activates microglia and alters their localization in the mouse embryo cerebral cortex

Sasaki

¹

,

Tome

²

,

Takei

³

2020

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Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

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“…Maternal immune activation (MIA) has been suggested to affect fetal brain development and to cause autism spectrum disorder (ASD) symptoms. Interleukin 17A (IL-17A) is a candidate mediator responsible for MIA-induced ASD pathogenesis [1][2][3][4]. In a commonly used mouse model of MIA, polyinosinic-polycytidylic acid [poly(I:C)], a viral mimic that potently induces inflammation, is administered to pregnant female mice [5,6].…”

Section: Introductionmentioning

confidence: 99%

Intraventricular IL-17A Administration Activates Microglia and Alters Their Localization in the Mouse Embryo Cerebral Cortex

Sasaki

¹

,

Tome

²

,

Takei

³

2020

Preprint

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Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

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IL-17a promotes sociability in mouse models of neurodevelopmental disorders

Cited by 198 publications

References 33 publications

Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder

Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder

Intraventricular IL-17A administration activates microglia and alters their localization in the mouse embryo cerebral cortex

Intraventricular IL-17A Administration Activates Microglia and Alters Their Localization in the Mouse Embryo Cerebral Cortex

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