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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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“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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“Interestingly, in two studies, the enhanced marbleburying behavior was ameliorated by IL-17A blocking, indicating that IL-17A has a role in repetitive ASD behavioral traits (36, 107).”
BackgroundModeling Autism-Related Disorders in Mice with Maternal Immune Activation (MIA)
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“In an experiment with genetically engineered mice, maternal interleukin-17a secreted by Th17 cells was observed to induce behavioral and cortical issues in their offspring, suggesting a possible role for the cytokine receptor interleukin-17a in the modulation of ASD (Choi et al., 2016).”
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“Interestingly, when IL17a was induced in pregnant dam mothers, the offspring exhibited an abnormal cortical development and autistic-phenotypes; even when IL-17a was administrated directly into the fetal brain [73].”
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“Moreover, a subtle increase in the number of buried marbles was observed in MIA C57BL6/J in late puberty, replicating previous findings that show repetitive behaviour in this strain (Schwartzer et al., 2013; Choi et al., 2016).”
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Autism spectrum disorder and severe social impairment associated with elevated plasma interleukin-8
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Estevez, K. J. N., Rondón-Ortiz, A. N., Nguyen, J., & Kentner, A. C. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.08.192 · Cited by 40
Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders
Balestrieri, E., Matteucci, C., Cipriani, C., Grelli, S., Ricceri, L., Calamandrei, G., & Vallebona, P. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236050 · Cited by 38
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Cytokine expression profiles in Autism spectrum disorder: A multi-center study from Turkey
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Chen, H., Chen, C., Mandhani, N., Short-Miller, J. C., Smucker, M. R., Sun, Y., & Kuan, C.-Y. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.1171-20.2020 · Cited by 40
“…the pathologic mechanisms of MIA, a commonly held view posits that MIA induces maternal effectors, such as IL-17a or IL-6, to directly attack the fetal brains, although permanent immune dysregulation in adult offspring was also reported (Smith et al., 2007; Hsiao et al., 2012; Choi et al., 2016).”
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“Considering perinatal inflammation is a potent modifier of neurodevelopment and offspring behavior (Hagberg et al., 2015; Choi et al., 2016; Reed et al., 2019), the role of inflammatory mechanisms in this capacity have been understudied.”
BackgroundKleeman, E. A., Gubert, C., & Hannan, A. J. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.03.006 · Cited by 41
“Notably, IL-17a released by T-helper 17 cells has been linked to ASD-like behaviours in offspring exposed to MIA [121].”
Sequential perturbations to mouse corticogenesis following in utero maternal immune activation
Canales, C. P., Estes, M. L., Cichewicz, K., Angara, K., Aboubechara, J. P., Cameron, S., Prendergast, K., Su-Feher, L., Zdilar, I., Kreun, E. J., et al. (2021) · eLife · doi:10.7554/elife.60100 · Cited by 43
“, 2015), with stereotypic dysplasia impacting lamination localized to the somatosensory cortex reported in one MIA model (Choi et al., 2016; Shin Yim et al., 2017).”
BackgroundResultInfluentialThe Role of Zinc and NMDA Receptors in Autism Spectrum Disorders
Lee, K. C., Mills, Z., Cheung, P. Y., Cheyne, J. E., & Montgomery, J. M. (2022) · Pharmaceuticals · doi:10.3390/ph16010001 · Cited by 42
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Self-citationInnate immune responses to pathogens at the maternal–fetal interface
Alippe, Y., Hatterschide, J., Coyne, C. B., & Diamond, M. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01191-0 · Cited by 41
“…including type I and type II interferons, IL-1β or tumour necrosis factor (TNF), interferes with normal early developmental programmes through toxicity to the pre-implantation embryo 127 and impaired differentiation and survival of trophoblasts 128,129 or neural progenitor cells 130,131 .”
Functional Implications of the IL-23/IL-17 Immune Axis in Schizophrenia
Debnath, M., & Berk, M. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0309-1 · Cited by 39
Sumoylation of RORγt regulates TH17 differentiation and thymocyte development
He, Z., Zhang, J., Huang, Z., Du, Q., Li, N., Zhang, Q., Chen, Y., & Sun, Z. (2018) · Nature Communications · doi:10.1038/s41467-018-07203-z · Cited by 38
Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders
Hughes, H. K., & Ashwood, P. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00627 · Cited by 41
“This cytokine is implicated in maternal immune activation (MIA) models of ASD, and without it ASD behaviors in MIA offspring were absent (45, 46).”
BackgroundMurakami, Y., Imamura, Y., Saito, K., Sakai, D., & Motoyama, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-49781-y · Cited by 40
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Being pregnant in the COVID‐19 pandemic: Effects on the placenta in all aspects
Seymen, C. M. (2021) · Journal of Medical Virology · doi:10.1002/jmv.26857 · Cited by 38
“Therefore, the potential risk of infected pregnant women and the fetus is not ignored; even these complications may be caused by the direct effect of the virus on mothers.18 If we return to the pregnancy cytokine storm, whose severity increases with COVID‐19, abnormal maternal inflammation as a result of the viral inf…”
BackgroundAsthma and posttraumatic stress disorder (PTSD): Emerging links, potential models and mechanisms
Allgire, E., McAlees, J. W., Lewkowich, I. P., & Sah, R. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.06.001 · Cited by 36
Avolio, E., Olivito, I., Rosina, E., Romano, L., Angelone, T., Bartolo, A. D., Scimeca, M., Bellizzi, D., D’Aquila, P., Passarino, G., et al. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.06.038 · Cited by 41
Murakami, Y., Imamura, Y., Kasahara, Y., Yoshida, C., Momono, Y., Fang, K., Sakai, D., Konishi, Y., & Nishiyama, T. (2023) · Cells · doi:10.3390/cells12071087 · Cited by 36
“Inhibited IL-17a signaling by antibody blockade of the cytokine in poly(I:C)-treated pregnant mice can prevent ASD-like phonotypes in the offspring [42].”
Powell, S. B., & Swerdlow, N. R. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad098 · Cited by 43
Shimada, A., & Hasegawa‐Ishii, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00017 · Cited by 38
Vergaelen, E., Schiweck, C., Steeland, K. V., Counotte, J., Veling, W., Swillen, A., Drexhage, H. A., & Claes, S. J. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.03.022 · Cited by 37
“The IL-17 receptor is expressed in many neural tissues and both neural damaging and beneficial effects of the cytokine have been described (Choi et al., 2016).”
BackgroundWu, Y., Qi, F., Song, D., He, Z., Zuo, Z., Yang, Y., Liu, Q., Hu, S., Wang, X., Zheng, X., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1252-z · Cited by 37
“Another possible reason is that, unlike in the polyinosinic-polycytidylic acid-induced autism model [60], IL-17a may be not sufficient to cause aberrant lamination and social deficits in this LPS-induced MIA model.”
Role of IL-6/RORC/IL-22 axis in driving Th17 pathway mediated immunopathogenesis of schizophrenia
Subbanna, M., Shivakumar, V., Talukdar, P. M., Narayanaswamy, J. C., Venugopal, D., Berk, M., Varambally, S. S., Venkatasubramanian, G., & Debnath, M. (2018) · Cytokine · doi:10.1016/j.cyto.2018.08.016 · Cited by 37
Nuclear Factor Kappa B in Autism Spectrum Disorder: A Systematic Review
Liao, X., & Li, Y. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104918 · Cited by 37
Gesù, C. M. D., Matz, L. M., & Buffington, S. A. (2021) · Neuroscience Research · doi:10.1016/j.neures.2021.05.003 · Cited by 47
Cognitive dysfunction in SLE: An understudied clinical manifestation
Mizrachi, M., Anderson, E., Carroll, K. R., Tehrani, N., Volpe, B. T., & Diamond, B. (2022) · Journal of Autoimmunity · doi:10.1016/j.jaut.2022.102911 · Cited by 39
Central Nervous System: (Immunological) Ivory Tower or Not?
Marin, I. A., & Kipnis, J. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.122 · Cited by 36
Environmental risk factors for autism spectrum disorders
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Microorganisms in the Placenta: Links to Early-Life Inflammation and Neurodevelopment in Children
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Holingue, C., Brucato, M. F., Ladd‐Acosta, C., Hong, X., Volk, H. E., Mueller, N. T., Wang, X., & Fallin, M. D. (2020) · Autism Research · doi:10.1002/aur.2411 · Cited by 37
“alterations in the immune profiles of offspring, in particular levels of IL-6 and IL-17α [Choi et al., 2016; Hsiao, McBride, Chow, Mazmanian, & Patterson, 2012; Mandal, Marzouk, Donnelly, & Ponzio, 2011; Smith, Li, Garbett, Mirnics, & Patterson, 2007].”
InfluentialHealing autism spectrum disorder with cannabinoids: a neuroinflammatory story
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The impact of (ab)normal maternal environment on cortical development
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“The abnormal inflammatory level has been proved to be significantly relevant to inducing autistic-like behaviors (34, 35).”
BackgroundMaternal Exposures Associated with Autism Spectrum Disorder in Jamaican Children
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“Upregulated expression of both IL-17a and TNFα also resulted in autism-like behaviors and deficits in social interaction in MIA-exposed offspring (Choi et al., 2016; Pendyala et al., 2017).”
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“Animal models have shown that activation of interleukin-17a (IL-17a) in the foetal brain, in response to maternal immune activation, is associated with behavioural disturbances and an abnormal cortical phenotype in affected offspring (26, 27).”
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Gut microbiota promotes immune tolerance at the maternal-fetal interface
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Pyramidal neuron growth and increased hippocampal volume during labor and birth in autism
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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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