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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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“Overall, MIA offspring show lower social behavior observed in the three-chamber social test, and they display altered USV (Careaga et al., 2017; Choi et al., 2016b; Hsiao et al., 2012; Hsiao et al., 2013; Malkova et al., 2012; Schwartzer et al., 2013; Wu et al., 2017).”
BackgroundAutism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets
Baranova, J., Dragunas, G., Botelho, M. C. S., Ayub, A. L. P., Bueno-Alves, R., Alencar, R. R., Papaiz, D. D., Sogayar, M. C., Ulrich, H., & Correa, R. G. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00882-7 · Cited by 63
Antoun, S., Ellul, P., Peyre, H., Rosenzwajg, M., Gressèns, P., Klatzmann, D., & Delorme, R. (2021) · Molecular Autism · doi:10.1186/s13229-021-00464-4 · Cited by 64
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“MIA down-regulates fetal microglial Gpr56 expression in an IL-17a–dependent manner MIA causes neurodevelopmental abnormalities in offspring through maternal interleukin-17a (IL-17a) ( 7 , 29 ).”
InfluentialAt the crux of maternal immune activation: Viruses, microglia, microbes, and IL‐17A
Otero, A. M., & Antonson, A. M. (2022) · Immunological Reviews · doi:10.1111/imr.13125 · Cited by 57
The brain is not mental! coupling neuronal and immune cellular processing in human organisms
Ciaunica, A., Shmeleva, E. V., & Levin, M. G. (2023) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2023.1057622 · Cited by 65
“Furthermore, cytokines produced by immune cells regulate neuronal function, influence brain development, and behavioral abnormalities (Yirmiya and Goshen, 2011; Bilbo and Schwarz, 2012; Choi et al., 2016; Kim et al., 2017).”
BackgroundRueda, C. M., Presicce, P., Jackson, C. M., Miller, L. A., Kallapur, S. G., Jobe, A. H., & Chougnet, C. A. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502613 · Cited by 60
Sex-dependent neurobiological features of prenatal immune activation via TLR7
Missig, G., Robbins, J. O., Mokler, E. L., McCullough, K. M., Bilbo, S. D., McDougle, C. J., & Carlezon, W. A. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0346-4 · Cited by 60
Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy
Sharma, S., Tiarks, G., Haight, J. A., & Bassuk, A. G. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.612073 · Cited by 58
Cristiano, C., Lama, A., Lembo, F., Mollica, M. P., Calignano, A., & Raso, G. M. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00184 · Cited by 60
“…of maternal fever; other studies evidence that viral and bacterial infections together with maternal gut microbiome alteration are associated with the development of ASD in offspring, through the activation of the maternal immune system (Lee et al., 2015; Choi et al., 2016; Mahic et al., 2017).”
BackgroundP2X7 receptors drive poly(I:C) induced autism-like behavior in mice
Horváth, G., Otrokocsi, L., Bekő, K., Baranyi, M., Kittel, Á., Fritz-Ruenes, P. A., & Sperlágh, B. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1895-18.2019 · Cited by 58
“, 2017), or indirect, through downstream Th17 cytokines, such as IL-17a, as described in other studies (Choi et al., 2016; Kim et al., 2017; Shin Yim et al., 2017).”
BackgroundResultInfluentialThe microbiome and immune memory formation
McCoy, K. D., Burkhard, R., & Geuking, M. B. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12273 · Cited by 62
The microbiota and immune‐mediated diseases: Opportunities for therapeutic intervention
Fitzgibbon, G., & Mills, K. H. G. (2020) · European Journal of Immunology · doi:10.1002/eji.201948322 · Cited by 59
Neuroendocrine-Immune Crosstalk Shapes Sex-Specific Brain Development
Arambula, S. E., & McCarthy, M. M. (2020) · Endocrinology · doi:10.1210/endocr/bqaa055 · Cited by 55
Gheissari, R., Liao, J., Garcia, E., Pavlovic, N., Gilliland, F. D., Xiang, A. H., & Chen, Z. (2022) · Toxics · doi:10.3390/toxics10080458 · Cited by 58
The majority of murine γδ T cells at the maternal–fetal interface in pregnancy produce IL‐17
Pinget, G. V., Corpuz, T. M., Stolp, J., Lousberg, E. L., Diener, K. R., Robertson, S. A., Sprent, J., & Webster, K. E. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.48 · Cited by 58
Gestational cytokine concentrations and neurocognitive development at 7 years
Ghassabian, A., Albert, P. S., Hornig, M., Yeung, E. H., Cherkerzian, S., Goldstein, R. B., Buka, S. L., Goldstein, J. M., & Gilman, S. E. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0112-z · Cited by 56
Karnik, M., Beeraka, N. M., Uthaiah, C. A., Nataraj, S. M., Bettadapura, A. D. S., Aliev, G., & Madhunapantula, S. V. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02399-6 · Cited by 56
Maternal stressors and the developmental origins of neuropsychiatric risk
Khambadkone, S. G., Cordner, Z. A., & Tamashiro, K. L. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2020.100834 · Cited by 61
How do established developmental risk-factors for schizophrenia change the way the brain develops?
Eyles, D. W. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01273-2 · Cited by 58
An integrated cytokine and kynurenine network as the basis of neuroimmune communication
Stone, T. W., Clanchy, F. I. L., Huang, Y., Chiang, N., Darlington, L. G., & Williams, R. O. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1002004 · Cited by 57
Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review
Yenkoyan, K. B., Mkhitaryan, M., & Bjørklund, G. (2024) · Current Medicinal Chemistry · doi:10.2174/0109298673252471231121045529 · Cited by 59
Estes, M. L., Prendergast, K., MacMahon, J. A., Cameron, S., Aboubechara, J. P., Farrelly, K., Sell, G. L., Haapanen, L. A. D., Schauer, J. D., Horta, A., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.04.061 · Cited by 59
Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder
Torres, A., Sweeten, T. L., Johnson, R. C., Odell, D., Westover, J. B., Bray‐Ward, P., Ward, D. C., Davies, C. J., Thomas, A. J., Croen, L., et al. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00463 · Cited by 52
TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology
Chen, C.-Y., Liu, H., & Hsueh, Y. (2016) · EMBO Reports · doi:10.15252/embr.201642586 · Cited by 54
IL ‐17 in neonatal health and disease
Lawrence, S. M., Ruoss, J. L., & Wynn, J. L. (2017) · American Journal of Reproductive Immunology · doi:10.1111/aji.12800 · Cited by 53
Careaga, M., Taylor, S. L., Chang, C., Chiang, A., Ku, K. M., Berman, R. F., de Water, J. V., & Bauman, M. D. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.06.014 · Cited by 53
Su, Z., Frost, E. L., Lammert, C. R., Przanowska, R. K., Lukens, J. R., & Dutta, A. (2020) · RNA Biology · doi:10.1080/15476286.2020.1721047 · Cited by 53
COVID-19 during Pregnancy and Postpartum:
Naidu, S. A. G., Clemens, R., Pressman, P., Zaigham, M., Kadkhoda, K., Davies, K. J. A., & Naidu, A. S. (2020) · Journal of Dietary Supplements · doi:10.1080/19390211.2020.1834049 · Cited by 57
Lynall, M.-E., Soskic, B., Hayhurst, J. D., Schwartzentruber, J., Levey, D. F., Pathak, G. A., Polimanti, R. A., Gelernter, J. E., Stein, M. B., Trynka, G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33885-7 · Cited by 53
Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains
Schwartzer, J. J., Careaga, M., Coburn, M., Rose, D. R., Hughes, H. K., & Ashwood, P. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.09.007 · Cited by 53
Nadeem, A., Ahmad, S. F., El‐Sherbeeny, A. M., Al-Harbi, N. O., Bakheet, S. A., & Attia, S. M. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.12.015 · Cited by 54
“Similarly, offspring born to immune activated mothers have higher Th17 related cytokines such as IL-17A/IL-6 not only in the brain but also in systemic compartment (Mandal et al., 2010; Choi et al., 2016; Schwartzer et al., 2013; Hsiao et al., 2012).”
BackgroundOrnoy, A., Weinstein‐Fudim, L., & Ergaz, Z. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20051074 · Cited by 57
“[30] found that maternal immune activation in mice affected fetal cerebral cortical development, inducing autistic-like behavior.”
BackgroundEshraghi, R. S., Davies, C., Iyengar, R., Perez, L., Mittal, R., & Eshraghi, A. A. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm10010027 · Cited by 58
“Crucially, as we will discuss further, TH-17 cells were implicated in the mechanism as IL-17a ablation protected neurodevelopmental abnormalities in ASD offspring [60,61].”
BackgroundNeuroimmune interactions in peripheral tissues
Klose, C. S. N., & Veiga‐Fernandes, H. (2021) · European Journal of Immunology · doi:10.1002/eji.202048812 · Cited by 55
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Modeling autism in non‐human primates: Opportunities and challenges
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“Other rodent models for ASD are risk factors induced such as maternal VPA-exposure [Rodier, 2002; Rinaldi, Kulangara, Antoniello, & Markram, 2007], maternal autoantibodies, and maternal immune activation (MIA) [Camacho et al., 2014; Choi et al., 2016; Kim et al., 2017].”
Luan, W., Hammond, L. A., Vuillermot, S., Meyer, U., & Eyles, D. W. (2018) · Scientific Reports · doi:10.1038/s41598-018-28090-w · Cited by 55
“In contrast, there was a significant main effect of MIA treatment on the mean ML positioning of mature (Nurr1+TH+) mesDAs (F(1,40) = 5.”
BackgroundMethodInfluentialLebovitz, Y., Kowalski, E., Wang, X., Kelly, C., Lee, M., McDonald, V., Ward, R., Creasey, M., Mills, W. A., Basso, E. K. G., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.07.025 · Cited by 55
Interleukin-17 as a key player in neuroimmunometabolism
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Contributions of monocytes to nervous system disorders
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“Maternal immune activation causes the elevation of IL-17 in maternal circulation, which is associated with autistic-like behaviors in offsprings [70].”
Kurschus, F. C., & Moos, S. (2017) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2017.06.010 · Cited by 51
Curran, E. A., O’Keeffe, G. W., Looney, A.-M., Moloney, G. M., Hegarty, S. V., Murray, D. M., Khashan, A. S., & Kenny, L. C. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0794-x · Cited by 50
“Recent studies have shown that dysregulation of circulating maternal cytokine signalling can lead to ASD-like behaviour in rodent offspring [15], and increased levels of maternal cytokines and chemokines during gestation are associated with ASD with intellectual disability in humans [16].”
Influential
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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