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The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring
Open accessAbstract
A T cell cause for autism?: The causes of autism spectrum disorder (ASD) are complex and not entirely clear. Alterations in the mother's immune system during pregnancy, especially during key early periods of fetal neurodevelopment, may play a role. Choi et al. provided infectious or inflammatory stimuli to pregnant mice, which resulted in of spring exhibiting behaviors reminiscent of ASD (see the Perspective by Estes and McAllister). A subset of T helper cells that make the cytokine interleukin-17a in the mothers caused cortical defects and associated ASD behaviors in offspring. Therapeutic targeting of interleukin-17a during gestation reduced ASD symptoms in offspring. Science , this issue p. 933 ; see also p. 919
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In the citing paper
“MIA can also induce more complex cortical phenotypes such as focal cortical dysplasia [81, 132], similar to those found in ASD [34] (Fig. 7).”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [132]
In the citing paper
“Also, cytoarchitecture heterogeneity is seen that is characteristic of ASD cases [34, 132].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [132]
In the citing paper
“The Choi and colleagues [132, 81] MIA ASD mouse model study showed that the same fetal MIA perturbation of littermates causes patches of focal cortical dysplasia that have marked heterogeneity, analogous to heterogeneity found in cortex in unrelated individual ASD cases postmortem [34] (Fig. 7).”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [132]
In the citing paper
“treatment of the anti-IL-17 antibody 2 days after MIA induction saw rescue of some phenotypes, such as USV calls and marble burying, but not others, including interaction deficits”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Choi et al, 2016
In the citing paper
“Given that IL-23 induces IL-17 and the importance of IL-17 for inducing the MIA model of autism (Choi et al, 2016)”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Choi et al, 2016
In the citing paper
“blocking key pathways prevents MIA-induced neural and behavioral abnormalities in ASD model systems.32”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [32]
In the citing paper
“MIA alters proliferation of cortical neural progenitor cells, laminar allocation of neurons, increased cortical thickness, increased cell density and patches of cortical dysplasia.32, 38, 42”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [32]
In the citing paper
“Increased systemic IL-17 during pregnancy leads to development of autism-like behaviors in pup offspring (Choi et al., 2016), which can also be regulated by maternal microbiota (Kim et al., 2017).”
From The IL-17 Family of Cytokines in Health and Disease (2019) · cites this paper as Choi et al., 2016
In the citing paper
“The implicated cytokine pathways include, and not limited to, IL-5, IL-15, IL-17, IL-17a, IL-10, IL-1b, TNF-α, TGF-β1 and IFNγ [12, 18, 65, 66].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [66]
In the citing paper
“Alterations of the host immune responses by gut microbiota are closely linked to ASD-related symptoms.”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [66]
In the citing paper
“A number of biomarkers that could connect to microbial profiles also have been identified in ASD, including alterations in serotonin levels, IL1β, and IL6.35, 44, 45, 46, 47”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [35]
In the citing paper
“Abnormal behaviors have also been reported in the absence of microbiota, including decreased anxiety-like behavior in the elevated plus maze21.”
From Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons (2020) · cites this paper as [21]
In the citing paper
“Alleviated anxiety-like behavior has been previously linked to the lack of microbiota21.”
From Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons (2020) · cites this paper as [21]
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Citations
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“Furthermore, Choi and colleagues have shown that MIA triggers a cascade of events including interleukin activation and microbiote modifications leading to abnormal cortical construction that is the final cause of the disease (Estes and McAllister, 2015; Choi et al., 2016; Kim et al., 2017).”
Li, Y., Dugyala, S., Ptacek, T., Gilmore, J. H., & Frӧhlich, F. (2018) · eNeuro · doi:10.1523/eneuro.0313-18.2018 · Cited by 27
“The elevated risk is associated with the activation of the maternal immune system (Jarskog et al., 1997; Gilmore and Jarskog, 1997; Urakubo et al., 2001; Brown et al., 2004; Gilmore et al., 2004, 2005; Smith et al., 2007; Abdallah et al., 2012; Choi et al., 2016).”
BackgroundEllul, P., Acquaviva, É., Peyre, H., Rosenzwajg, M., Gressèns, P., Klatzmann, D., & Delorme, R. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01843-y · Cited by 30
“In MIA-mice model, interleukin 6 (IL-6) and interleukin 17 (IL17) secretion during pregnancy mediates the occurrence of ASDlike behavior in pups [60, 61].”
BackgroundGuardians of the brain: how a special immune system protects our grey matter
Kwon, D. (2022) · Nature · doi:10.1038/d41586-022-01502-8 · Cited by 30
Immune Responses to SARS-CoV-2 in Pregnancy: Implications for the Health of the Next Generation
Shook, L. L., Fourman, L. T., & Edlow, A. G. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2200414 · Cited by 27
Lin, T., Lu, C.-C., Chen, T.-W., Huang, C., Lu, J., Lai, W.-F., Wu, T., Lai, C., Lai, H., & Chen, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113070 · Cited by 29
“Previous studies indicated that prenatal MIA could increase the levels of interleukin17A (IL-17A), which initiated immune-primed phenotypes in offspring that exhibited autism-like phenotypes and increased susceptibility to develop intestinal inflammation later in life [38,39].”
BackgroundThe impact of maternal immune activation on embryonic brain development
McEwan, F., Glazier, J. D., & Hager, R. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1146710 · Cited by 30
“However, there are differences in the direction of density change (Table 3; Gallagher et al., 2013; Chao et al., 2016; Choi et al., 2016; Wu et al., 2018; Ben-Reuven and Reiner, 2021; Canales et al., 2021), most likely due to minor discrepancies in timing of MIA induction as well as the gestational time point of lamin…”
BackgroundHsueh, P., Lin, H., Wang, H. ‐., Liu, C., Ni, W.-F., Liu, J. ‐., Chang, H., Sun, D., Chen, Y. ‐., & Chen, Y. (2018) · Genes Brain & Behavior · doi:10.1111/gbb.12479 · Cited by 27
“The expression of both IL-6 and IL-17a is tightly associated with ASD-like behaviors in animals or patients.(13,14,55,56) Our MIA offspring models showed the overexpression of IL-6 but did not display an upregulation of IL-17a expression in the brains.”
BackgroundVigli, D., Palombelli, G., Fanelli, S., Calamandrei, G., Canese, R., Mosca, L., Scattoni, M. L., & Ricceri, L. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.05.009 · Cited by 28
Kimmel, M., Verosky, B. G., Chen, H. J., Davis, O., & Gur, T. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.11.014 · Cited by 30
PLASTAMINATION: Outcomes on the Central Nervous System and Reproduction
Santoro, A., Marino, M., Vandenberg, L. N., Szychlinska, M. A., Lamparelli, E. P., Scalia, F., Rocca, N. D., D’Auria, R., Pastorino, G. M. G., Porta, G. D., et al. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240216085947 · Cited by 28
Reimagining the meninges from a neuroimmune perspective: a boundary, but not peripheral
Zhang, X., Liu, L., Chai, Y., Zhang, J., Deng, Q., & Chen, X. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03286-2 · Cited by 31
Hollander, E., Uzunova, G., Taylor, B. P., Noone, R., Racine, E., Doernberg, E. A., Freeman, K. D., & Ferretti, C. J. (2018) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2018.1523561 · Cited by 24
“Both T helper 17 (TH17) cells and the effector cytokine interleukin-17a (IL-17a), are present in mothers who have MIA-induced behavioural abnormalities in their offspring (Choi et al. 2016; Careaga et al. 2017).”
BackgroundTsukada, T., Shimada, H., Sakata‐Haga, H., Iizuka, H., & Hatta, T. (2018) · Congenital Anomalies · doi:10.1111/cga.12323 · Cited by 27
“The first concern is that different activators are used to induce MIA.”
BackgroundInfluentialPotasiewicz, A., Gzieło, K., Popik, P., & Nikiforuk, A. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.113113 · Cited by 27
Matute, J. D., Finander, B., Pépin, D., Ai, X., Smith, N. P., Li, J. Z., Edlow, A. G., Villani, A., Lerou, P. H., & Kalish, B. T. (2021) · Pediatric Research · doi:10.1038/s41390-021-01793-z · Cited by 26
Sickness and the Social Brain: How the Immune System Regulates Behavior across Species
Devlin, B. A., Smith, C. J. W., & Bilbo, S. D. (2021) · Brain Behavior and Evolution · doi:10.1159/000521476 · Cited by 30
“…this effect is mediated by the pro-inflammatory cytokine Interleukin-17A (IL-17a), as blocking this cytokine in the mother prevents the effects of Poly:IC, demonstrating that activating (and inhibiting) the immune system during development influences later-life social behavior [Choi et al., 2016].”
BackgroundReelin cells and sex‐dependent synaptopathology in autism following postnatal immune activation
Ardalan, M., Chumak, T., Quist, A., Hermans, E. C., Rafati, A. H., Gravina, G., Shiadeh, S. M. J., Svedin, P., Alabaf, S., Hansen, B., et al. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15859 · Cited by 26
“natal immune activation has been suggested to underlie autistic-like behaviours (Choi et al., 2016).”
BackgroundAlmutairi, M. M., Nadeem, A., Ansari, M. A., Bakheet, S. A., Attia, S. M., Albekairi, T. H., Alhosaini, K. A., Algahtani, M., Alsaad, A. M. S., Al‐Mazroua, H. A., et al. (2022) · NeuroToxicology · doi:10.1016/j.neuro.2022.06.007 · Cited by 26
Maternal pregnancy-related infections and autism spectrum disorder—the genetic perspective
Nudel, R., Thompson, W. K., Børglum, A. D., HOUGAARD, D. M., Mortensen, P. B., Werge, T. M., Nordentoft, M., & Benros, M. E. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02068-9 · Cited by 29
Boktor, J. C., Adame, M. D., Rose, D. R., Schumann, C. M., Murray, K. D., Bauman, M. D., Careaga, M., Mazmanian, S. K., Ashwood, P., & Needham, B. D. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01752-y · Cited by 27
Carbone, E., Buzzelli, V., Manduca, A., Leone, S., Rava, A., & Trezza, V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043920 · Cited by 25
Wojcik, S., Bernatsky, S., Platt, R. W., Pineau, C. A., Clarke, A. E., Fombonne, E. J., Bérard, A., & Vinet, É. (2017) · Arthritis Care & Research · doi:10.1002/acr.23235 · Cited by 26
“In a recent experiment using IL-17A, both genetic mutants and blocking antibodies in mice showed that T helper 17 (TH17) cells and the effector cytokine IL-17A are required in mothers for MIAinduced behavioral abnormalities in offspring (13).”
BackgroundImmunity and ultrasonic vocalization in rodents
Jouda, J., Wöhr, M., & del Rey, A. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13931 · Cited by 28
Overview of genetic models of autism spectrum disorders
Patel, J., Lukkes, J. L., & Shekhar, A. (2018) · Progress in brain research · doi:10.1016/bs.pbr.2018.10.002 · Cited by 29
T cells in the brain inflammation
Yoshimura, A., Ohyagi, M., & Ito, M. (2022) · Advances in immunology · doi:10.1016/bs.ai.2022.10.001 · Cited by 29
Ding, X., Zhou, Y., Qiu, X., Xu, X., Hu, X., Qin, J., Chen, Y., Zhang, M., Ke, J., Liu, Z., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.101974 · Cited by 24
“37 Based on the adverse pregnancy outcomes observed in clinical cases of SLE and SLE mouse models, we opted to administer poly(I:C) at E10.”
Sun, P., Wang, M., Chai, X., Liu, Y., Li, L., Zheng, W., Chen, S., Zhu, X., & Zhao, S. (2025) · Nature Communications · doi:10.1038/s41467-025-57414-4 · Cited by 26
García-Valtanen, P., van Diermen, B. A., Lakhan, N., Lousberg, E. L., Robertson, S. A., Hayball, J. D., & Diener, K. R. (2020) · American Journal of Reproductive Immunology · doi:10.1111/aji.13260 · Cited by 26
Complications and outcomes of SARS-CoV-2 in pregnancy: where and what is the evidence?
Trad, A. T. A., Ibirogba, E. R., Elrefaei, A., Narang, K., Tonni, G., Picone, O., Suy, A., Carreras, E., Kilby, M. D., & Ruano, R. (2020) · Hypertension in Pregnancy · doi:10.1080/10641955.2020.1769645 · Cited by 25
“In addition, negative outcomes have been described in association with the presence of excess cytokines in pregnant patients: pregnancy loss and preterm delivery have been correlated to high concentrations of systemic cytokines in women with malaria (26) and maternal immune activation with an increase in IL-17 levels…”
BackgroundZhao, W., Gu, N.-H., Li, Z., Wang, G., Cheng, C. Y., & Sun, F. (2020) · Aging · doi:10.18632/aging.104061 · Cited by 25
“The movement of mice and the time spent in each chamber were measured using a Noldus system as described [40].”
MethodEarly and Late Corrections in Mouse Models of Autism Spectrum Disorder
Chung, C., Shin, W., & Kim, E. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.07.021 · Cited by 23
Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder
Casey, S., Carter, M., Looney, A.-M., Livingstone, V., Moloney, G. M., O’Keeffe, G. W., Taylor, R. S., Kenny, L. C., McCarthy, F. P., McCowan, L. M. E., et al. (2021) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-021-05271-7 · Cited by 28
JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder
Li, H., Wang, X., Hu, C., Li, H., Xu, Z., Lei, P., Luo, X., & Hao, Y. (2022) · Frontiers in Neuroinformatics · doi:10.3389/fninf.2022.800079 · Cited by 25
“Recent studies have shown that IL-17 is a key contributor to neurodevelopmental abnormalities in MIA offspring (Choi et al., 2016).”
BackgroundIL-17 and TNF-β: Predictive biomarkers for transition to psychosis in ultra-high risk individuals
Ouyang, L., Li, D., Li, Z., Ma, X., Liu, Y., Fan, L., Yang, Z., Zhang, Z., Li, C., Hé, Y., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1072380 · Cited by 24
“IL-17 can mediate various aspects of prenatal immune activation (63).”
BackgroundLoewen, S. M., Chavesa, A. M., Murray, C. J., Traetta, M. E., Burns, S. E., Pekarik, K. H., & Tremblay, M. (2023) · Developmental Neuroscience · doi:10.1159/000530185 · Cited by 28
Kaminski, V. D. L., Michita, R. T., Ellwanger, J. H., Veit, T. D., Schuch, J. B., Riesgo, R. D. S., Roman, T., & Chies, J. A. B. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e15593 · Cited by 29
“: IL-2, IL-6, and IL-17a) during pregnancy were associated with a higher risk of ASD development in the offspring [80,81].”
BackgroundCrosstalk Between the Microbiome and Gestational Immunity in Autism-Related Disorders
Paysour, M. J., Bolte, A. C., & Lukens, J. R. (2019) · DNA and Cell Biology · doi:10.1089/dna.2019.4653 · Cited by 25
“IL-17a, an inflammatory cytokine generated downstream of IL-6, has also recently been identified to be a critical instigator of behavioral and cortical abnormalities in the MIA model (Choi et al., 2016; Shin Yim et al., 2017).”
BackgroundHill, R., Gibbons, A., Suwakulsiri, W., Taseska, A., Darke, H., Malhotra, A. K., Yee, H., Fahey, M. C., Hunt, R. W., Lim, I., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02808-x · Cited by 25
“Indeed, mouse model studies have shown that blocking speci fi c pro-in fl ammatory cytokines, such as interleukin-6 (IL-6) and Interleukin-17A (IL-17A), following maternal exposure to a viral mimetic can prevent the emergence of adverse behavioural outcomes in offpring [14, 15].”
InfluentialNeural stem cells attacked by Zika virus
Nguyen, H. N., Qian, X., Song, H., & Ming, G. (2016) · Cell Research · doi:10.1038/cr.2016.68 · Cited by 23
Microglia in animal models of autism spectrum disorders
Andoh, M., Ikegaya, Y., & Koyama, R. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.04.012 · Cited by 25
Alhosaini, K. A., Ansari, M. A., Nadeem, A., Bakheet, S. A., Attia, S. M., Alhazzani, K., Albekairi, T. H., Al‐Mazroua, H. A., Mahmood, H. M., & Ahmad, S. F. (2021) · Brain Sciences · doi:10.3390/brainsci11020249 · Cited by 23
“IL-17A promotes sociability in the mouse model of neurodevelopmental disorder [26], and increased production of IL-17A in pregnant mothers can promote autism-like phenotypes in offspring [27,28].”
BackgroundPsychobiotics as a novel strategy for alleviating anxiety and depression
Zou, R., Tian, P., Xu, M., Zhu, H., Zhao, J., Zhang, H., Chen, W., & Wang, G. (2021) · Journal of Functional Foods · doi:10.1016/j.jff.2021.104718 · Cited by 25
Maternal Immune Activation Hypotheses for Human Neurodevelopment: Some Outstanding Questions
O’Connor, T. G., & Ciesla, A. A. (2021) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2021.10.006 · Cited by 24
γδ T Cells in Brain Homeostasis and Diseases
Park, J. H., Kang, I., & Lee, H. K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.886397 · Cited by 25
“Poly I:C-induced maternal immune activation (MIA) mimicking infections showed autism-like behavior of progenies (85).”
Background
Metadata
- Authors
- Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., Hoeffer, C. A., Littman, D. R., & Huh, J. R.
- Affiliations
- McGovern Institute for Brain Research (US)
- University of Colorado Boulder (US)
- University of Massachusetts Chan Medical School (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Choi, Gloria B.
- Yim, Yeong S.
- Wong, Helen
- Hoeffer, Charles A.
- Littman, Dan R.
- Huh, Jun R.
- ORCID
- Venue
- Science
- Published
- 2016-02-26
- Volume
- 351
- Issue
- 6276
- Pages
- 933-939
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4782964
- OpenAlex
- W2253802357
- Cited by
- 1,214
- References
- 47
- Citations by year
- 2026: 108 · 2025: 137 · 2024: 147 · 2023: 123 · 2022: 155 · 2021: 136 · 2020: 109 · 2019: 82 · 2018: 97 · 2017: 65 · 2016: 50
- FWCI
- 62.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- Simons Foundation Autism Research Initiative
- Simons Foundation to the Simons Center for the Social Brain at Massachusetts Institute of Technology
- Robert Buxton
- National Research Foundation of Korea (MEST-35B-2011-1-E00012, NRF-2014R1A1A1006089)
- Crohn’s and Colitis Foundation of America (329388)
- Smith Family Foundation
- Searle Scholars Program
- Alzheimer's Association (MNIRGDP-12-258900)
- Brain and Behavior Research Foundation (NARSAD) (21069)
- NIH (F31NS083277, R00DK091508, R01NS086933)
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- maternal immune activation, autism spectrum disorder, IL-17A, RORγt, Th17 cells, maternal viral infection, autism-like behavior, fetal brain, prenatal inflammation
- MeSH terms
- Autism Spectrum Disorder, Retinoic Acid Receptor gamma, Animals, Behavior, Animal, Behavioral Symptoms, Cerebral Cortex, Female, Male, Maternal-Fetal Exchange, Mutation, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, RNA, Messenger, Signal Transduction, Receptors, Retinoic Acid, Antibodies, Blocking, Interleukin-17, Mice, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells
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