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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
Cites
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Self-citationInduction of Intestinal Th17 Cells by Segmented Filamentous Bacteria
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“Some studies have reported reduced USV calls upon MIA (8, 31), but these opposite effects may reflect differences in methodological approaches, including dose and number of exposures to poly(I:C) as well as timing of poly(I:C) administration.”
BackgroundNeuronal subtype specification in the cerebral cortex
Molyneaux, B. J., Arlotta, P., Menezes, J. R. L., & Macklis, J. D. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2151 · Cited by 1,704 · cited 1×
“5 as well as in the adult brain using antibodies specific for proteins expressed in the cortex in a layer-specific manner (25): Special AT-rich sequencebinding protein 2 (SATB2) (26), T-brain-1 (TBR1) (27), and chicken ovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2) (28).”
BackgroundMaternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Smith, S. E. P., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2178-07.2007 · Cited by 1,605 · cited 6×
“3C), consistent with previous studies (7, 29).”
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Self-citationFunctional Specialization of Interleukin-17 Family Members
Iwakura, Y., Ishigame, H., Saijo, S., & Nakae, S. (2011) · Immunity · doi:10.1016/j.immuni.2011.02.012 · Cited by 1,289 · cited 1×
“To determine if IL-17a acts on receptors in the mother or the fetus to induce the MIA phenotype, we injected poly(I:C) into IL-17Ra WT, HET or KO mothers that had been bred to IL-17Ra WT or HET males (39).”
MethodEnglund, C., Fink, A., Lau, C., Pham, D., Daza, R. A. M., Bulfone, A., Kowalczyk, T., & Hevner, R. F. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2899-04.2005 · Cited by 1,261 · cited 12×
“Co nt an tiIL -1 7a PBS Poly(I:C) Co nt an tiIL -1 7a 0 500 1000 1500 2000 To ta l d is ta nc e m ov ed ( cm ) 2500 0 100 200 300 400 U S V in de x Co nt an ti- IL -1 7a PBS Poly(I:C) **** ** Co nt an ti- IL -1 7a 0 20 40 60 80 % In te ra ct io n 100 Social Inanimate ** * ** Co nt an ti- IL -1 7a PBS Poly(I:C) Co nt a…”
BackgroundInfluentialPeñagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H., Sonnenblick, L. I., Gruver, R., Almajano, J., Bragin, A., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.040 · Cited by 1,075 · cited 1×
“Furthermore it is worthwhile to note that the loss of certain genes that induce ASD-like phenotypes were also found with defects in cortical lamination (41, 42).”
BackgroundMaternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders
Atladóttir, H. Ó., Thorsen, P., Østergaard, L., Schendel, D. E., Lemcke, S., Abdallah, M., & Parner, E. T. (2010) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-010-1006-y · Cited by 916
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Maternal brain reactive antibodies profile in autism spectrum disorder: an update
Bagnall-Moreau, C., Spielman, B. P., & Brimberg, L. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02335-3 · Cited by 27
Translational Neuroscience Approaches to Understanding Autism
Veenstra-VanderWeele, J. M., O’Reilly, K. C., Dennis, M. Y., Uribe‐Salazar, J. M., & Amaral, D. G. (2023) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20230153 · Cited by 25
Role of Maternal Immune Factors in Neuroimmunology of Brain Development
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“IL-17 increases BBB permeability and produces neuroinflammation by evoking glial cells to produce inflammatory cytokines, which makes the brain susceptible to destructive immune cells and anticipating ASD in offspring [42–44].”
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“MIA triggers heightened maternal pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6 and IL-17 α , which can interfere with fetal brain development (Choi et al., 2016; Smith et al., 2007).”
Bian, Q., Chen, Y., Zhang, J., Du, X., Zhou, Y., Zhang, Q., Ding, C., Wei, H., & Fu, B. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.028 · Cited by 22
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“Also, IL-6 and IL-17A levels in ZIKV group did not change significantly throughout the experiment (S2 Fig); the same was found for maternal IL-1β, IL-8, IL-10, IL-12, IL-13, IFN-β, and IFN-γ (S2 Fig).”
ResultInfluentialSickness and the Social Brain: Love in the Time of COVID
Smith, C. J. W., & Bilbo, S. D. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.633664 · Cited by 22
“Immune challenges during the perinatal period disrupt adult social functioning in bothmales and females, but these effects appear to depend on a variety of factors including developmental timing of the challenge, drug dose, and the nature of the challenge itself (30, 68, 69, 111, 178, 179).”
BackgroundLocal and long-range circuit elements for cerebellar function
Xiao, L., & Scheiffele, P. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.12.016 · Cited by 22
“While most studies in model systems have focused on cortical cells and circuits [49, 50] there is evidence that some cytokines are elevated in granule cells in brain sections from ASD patients and that elevation of IL-6 in the rodent granule cells results in abnormalities [51] [52, 53].”
BackgroundLacorcia, M., & da Costa, C. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02960 · Cited by 21
“Mouse models of viral infection during gestation using poly I:C as an analog for viral double stranded (ds)RNA have demonstrated mostly adverse effects on offspring behavior triggered by the increase in pro-inflammatory cytokines, such as IL-6 and IL-17A (21).”
Markova, N. (2019) · Scientific Reports · doi:10.1038/s41598-019-49768-9 · Cited by 20
Church, J. S., Tamayo, J. M., Ashwood, P., & Schwartzer, J. J. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.12.014 · Cited by 22
“5 resulted in social behavior deficits and increased marble burying behavior driven by increases in maternal IL-17A cytokine levels (Choi et al. 2016).”
BackgroundMiyajima, H., Itokazu, T., Tanabe, S., & Yamashita, T. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04064-1 · Cited by 23
Emerging Knowledge of the Neurobiology of COVID-19
Butler, M., Cross, B., Hafeez, D., Lim, M. F., Morrin, H., Rengasamy, E. R., Pollak, T. A., & Nicholson, T. R. (2021) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2021.11.001 · Cited by 20
“noted, SARS-CoV-2 may elicit a Th17 (IL-17) immune response, and studies in mouse models show administration of IL-17 produces an autismlike phenotype and behavior in offspring.(107) Similarly, the physiologic, metabolic, and endocrine correlates of maternal physiologic stress, which may occur in the context of a vira…”
Scott, E. P., Breyak, E., Nishinakamura, R., & Nakagawa, Y. (2022) · Glia · doi:10.1002/glia.24192 · Cited by 24
“In addition, maternal immune activation or inactivation, both of which alter microglia, also disrupts normal brain development (Bilbo et al., 2018; Choi et al., 2016; Cunningham et al., 2013; Tronnes et al., 2016).”
BackgroundA Wholistic View of How Bumetanide Attenuates Autism Spectrum Disorders
Delpire, E. J., & Ben‐Ari, Y. (2022) · Cells · doi:10.3390/cells11152419 · Cited by 20
Current advancements of modelling schizophrenia using patient-derived induced pluripotent stem cells
Dubonyte, U., Asenjo-Martínez, A., Werge, T. M., Lage, K., & Kirkeby, A. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01460-2 · Cited by 23
“A mouse model using polyriboinosinic-polyribocytidilic acid (PolyIC) as an MIA-inducer similarly shows altered social interaction, cognitive decline and neurodevelopmental impairments in the affected offspring [27, 148].”
MethodHaddad, F. L., Oliveira, C. D., & Schmid, S. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1160243 · Cited by 22
“Beyond behavioral phenotypes, both Poly I:C MIA offspring and Cntnap2−/− mice show similar cellular and molecular brain phenotypes including disorganized cortical layering (Peñagarikano et al., 2011; Choi et al., 2016; Coutinho et al., 2017), decreased expression of Parvalbumin in the hippocampus (Abazyan et al.”
BackgroundOne messenger shared by two systems: How cytokines directly modulate neurons
Yang, L., Huh, J. R., & Choi, G. B. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102708 · Cited by 25
Self-citationMaternal BPAF exposure impaired synaptic development and caused behavior abnormality in offspring
Wu, X., Li, S., Ni, Y., Qi, C., Bai, S., Xu, Q., Fan, Y., Ma, X., Lu, C., Du, G., et al. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.114859 · Cited by 21
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Tamang, M. K., Ali, A. A., Pértile, R. A. N., Cui, X., Alexander, S., Nitert, M. D., Palmieri, C., & Eyles, D. W. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02513-3 · Cited by 25
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“For example, increased levels of IL-6 during pregnancy induced the secretion of IL-17a, which increased the IL-17 receptor levels in the brains of offspring, leading to ASD-related cortical and behavioral abnormalities [72, 74].”
BackgroundKelley, M. H., Wu, W., Lei, J., McLane, M., Xie, H., Hart, K. D., Pereira, L. M., Burd, I. D., & Maylie, J. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0951-1 · Cited by 21
“Additionally, maternal inflammation has been linked with increased prevalence of autism and experimental animal models mimicking maternal infection and inflammation result in autism-like phenotypes [10, 11].”
Maternal immune activation alters brain microRNA expression in mouse offspring
Sunwoo, J., Jeon, D., Lee, S., Moon, J., Yu, J., Park, D.-K., Bae, J., Lee, D. Y., Kim, S. W., Jung, K., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.652 · Cited by 20
“Poly (I:C) administration strongly induces pro-inflammatory cytokines, and among these, interleukin (IL)-6 and IL-17a are key mediators for abnormal cortical development and behavioral phenotypes in the MIA model.(14,15) Although numerous preclinical studies have been conducted using the MIA animal model, little infor…”
BackgroundSelf-citationMaternal Antibody and ASD: Clinical Data and Animal Models
Gata-Garcia, A., & Diamond, B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01129 · Cited by 22
Paraschivescu, C., Barbosa, S., Lorivel, T., Glaichenhaus, N., & Davidovic, L. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231609 · Cited by 22
“As for emitted USV, Choi and his co-workers have found increased numbers of USVs produced by MIA pups [16, 48].”
BackgroundMethodPrieto‐Villalobos, J., Alvear, T. F., Liberona, A., Lucero, C. M. J., Martínez-Araya, C. J., Balmazabal, J., Inostroza, C. A., Ramírez, G., Gómez, G. I., & Orellana, J. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179503 · Cited by 21
“This evidence harmonizes with the critical role of IL-1β and IL-17 A on adult brain abnormalities observed following maternal immune activation in rodents [35,36].”
ResultInfluentialPrenatal Immune Stress: Its Impact on Brain Development and Neuropsychiatric Disorders
Vasistha, N. A., & Sawa, A. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-024048 · Cited by 20
Gut-immune-brain dysfunction in Autism: Importance of sex
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Ribeiro, R., Nicoli, J. R., Santos, G., & dos Santos, J. L. (2019) · Nutritional Neuroscience · doi:10.1080/1028415x.2019.1660485 · Cited by 26
Guma, E., Snook, E., Spring, S., Lerch, J. P., Nieman, B. J., Devenyi, G. A., & Chakravarty, M. M. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102868 · Cited by 20
“…acid sodium salt TLR ligand tested; Sigma Aldrich) (5 mg/kg, intraperitoneally) at GD 9 (POL E; 6 dams), (Brown et al., 2004) 0.9% sterile NaCl solution at GD 9 (SAL E; 5 dams), (Selten et al., 1997) poly I: C at GD 17 (POL L; 6 dams), or (Choi et al., 2016) saline at GD 17 (SAL L; 4 dams).”
BackgroundInfluentialUsui, N., Matsumoto, K., Koyama, Y., Kobayashi, Y., Nakamura, Y., Kobayashi, H., & Shimada, S. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.872302 · Cited by 19
“Poly(I:C) Administration Poly(I:C) was administered as described previously (17).”
BackgroundMethodInfluentialLactiplantibacillus plantarum N-1 improves autism-like behavior and gut microbiota in mouse
Qiu, Z., Luo, D., Yin, H., Chen, Y., Zhou, Z., Zhang, J., Zhang, L., Xia, J., Xie, J., Sun, Q., et al. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1134517 · Cited by 22
“In animal models, poly (I:C) injection during pregnancy results in increased release of local cytokines, including IL-17a (Choi et al., 2016), which can recapitulate the key symptoms of ASD and be used to examine the efficacy of the candidate remedies, especially A B D E C FIGURE 5 The alpha diversity assessed by Chao…”
BackgroundInfluentialProlonged STAT1 activation in neurons drives a pathological transcriptional response
Clark, D. N., O’Neil, S. M., Xu, L., Steppe, J. T., Savage, J. T., Raghunathan, K., & Filiano, A. J. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578168 · Cited by 19
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“In mice, MIA directly triggers autistic-like symptoms through an effect on neuronal cytokine receptors in the cerebral cortex 3 .”
BackgroundGenetic relationship between the immune system and autism
Arenella, M., Fanelli, G., Kiemeney, L. A. L. M., McAlonan, G. M., Murphy, D., & Bralten, J. (2023) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2023.100698 · Cited by 23
“For instance, xperiments in animal models of MIA demonstrated that genetic regulators of immunity, such as interleukin-17 pathway genes, may mediate the effects of MIA on the offspring behaviours (Choi et al., 2016; Lombardo et al., 2018; Smith et al., 2007; Traglia et al., 2018).”
BackgroundImmunomodulatory Effects of Clozapine: More Than Just a Side Effect in Schizophrenia
Amerio, A., Magnani, L., Arduino, G., Fesce, F., de Filippis, R., Parise, A., Costanza, A., Nguyen, K. D., Saverino, D., Berardis, D. D., et al. (2023) · Current Neuropharmacology · doi:10.2174/1570159x22666231128101725 · Cited by 21
“Importantly, recent experimental studies show that events occurring during early ontogenetic phases of an organism's development, such as maternal infections, can result in long-term alterations in microglia physiology and in an abnormal brain development in the offspring [20, 21].”
BackgroundMukhtar, I. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111135 · Cited by 22
The Role of Parvalbumin Interneurons in Autism Spectrum Disorder
Yao, Y., & Li, Q. (2024) · Journal of Neuroscience Research · doi:10.1002/jnr.25391 · Cited by 20
“During MIA exposure, the levels of proinflammatory cytokines, such as IL16, IL-17a, and TNFα, as well as activation of microglia, were elevated in both maternal serum and fetal brain (Choi et al. 2016; Smith et al. 2007).”
Outcomes in Children Born to Women with Rheumatic Diseases.
Vinet, É., & Bernatsky, S. (2017) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2016.12.006 · Cited by 20
SRC3 is a co-factor for RORγt in Th17 differentiation but not thymocyte development
He, Z.-H., Zhang, J., Du, Q., Xu, J.-M., Gwack, Y., & Sun, Z.-M. (2018) · Journal of Immunology · doi:10.4049/jimmunol.1801187 · Cited by 18
Jaini, R., Wolf, M. R., Yu, Q., King, A. T., Frazier, T. W., & Eng, C. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01472-x · Cited by 21
Lins, B. R. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100297 · Cited by 22
“…studies test offspring in adulthood, autism-focussed research assess behaviours in young animals and report reduced sociability and play, altered ultrasonic vocalizations, and repetitive behaviours such as increased marble-burying (al-Haddad et al., 2019; Choi et al., 2016; Shin Yim et al., 2017).”
Yang, Y., Wang, B., Zhong, Z., Chen, H., Ding, W., & Hoi, M. P. M. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114711 · Cited by 21
López‐Aranda, M. F., Chattopadhyay, I., Boxx, G. M., Fraley, E., Silva, T. K., Zhou, M., Phan, M., Herrera, I., Taloma, S. E., Mandanas, R., et al. (2021) · Science Advances · doi:10.1126/sciadv.abf2073 · Cited by 19
Zhang, L., Lin, C., Zhu, J., He, Y., Zhan, M., Xia, X., Yang, N., Yang, K., Wang, Y., Zhong, Z., et al. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109715 · Cited by 20
Neuroinflammation and Neurotransmission Mechanisms Involved in Neuropsychiatric Disorders
Leite, J. A., Orellana, A. M., Kinoshita, P. F., de Mello, N. P., Scavone, C., & Kawamoto, E. M. (2017) · InTech eBooks · doi:10.5772/intechopen.69343 · Cited by 20
“However, the role of IL‐17 is still obscure in ASD despite some temptations of explanation in rodent maternal immune activation (MIA) models [122].”
Backgroundγδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde
Li, Y., Zhang, Y., & Zeng, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.656097 · Cited by 20
“IL17, a key cytokine for inflammation, has also been discovered to administrate the fetal brain development and behavioral abnormalities (23, 24).”
BackgroundAberrant IL-17 Levels in Rodent Models of Autism Spectrum Disorder: A Systematic Review
Thawley, A., Veneziani, L. P., Rabelo‐da‐Ponte, F. D., Riederer, I., Mendes‐da‐Cruz, D. A., & Bambini-Júnior, V. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.874064 · Cited by 20
“Choi, 2016 (16) mice C57BL/6N male NS MIA 20 Poly(I:C) i.”
BackgroundMethodResultInfluentialImmune-Triggered Forms of Plasticity Across Brain Regions
Hikosaka, M., Kawano, T., Wada, Y., Maeda, T., Sakurai, T., & Ohtsuki, G. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.925493 · Cited by 21
“Regarding disease association with the brain immunity, excessive inflammatory cytokines, disruption of brain vasculature systems, the proliferation of activated immune cells in the parenchyma, and malformation of neurons are observed in the various animal models emerging the symptoms of psychiatric disorders (Hopkins…”
BackgroundAngrand, L., Masson, J.-D., Rubio‐Casillas, A., Nosten‐Bertrand, M., & Crépeaux, G. (2022) · Toxics · doi:10.3390/toxics10090518 · Cited by 20
Microbes and Mental Illness: Past, Present, and Future
Bransfield, R. C., Mao, C., & Greenberg, R. (2023) · Healthcare · doi:10.3390/healthcare12010083 · Cited by 23
The role of the placenta-brain axis in psychoneuroimmune programming
Gumusoglu, S. B. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100735 · Cited by 21
“This complements other preclinical reports that feto-placental T helper 17 (TH17) cells are a critical component of maternal immune activation impacts on offspring brain outcomes (Choi et al., 2016; Estes et al., 2016).”
ResultContext-dependent role of group 3 innate lymphoid cells in mucosal protection
Araújo, L. P., Edwards, M., Irie, K., Huang, Y., Kawano, Y., Tran, A., Michele, S. D., Bhagat, G., Wang, H. H., & Ivanov, I. I. (2024) · Science Immunology · doi:10.1126/sciimmunol.ade7530 · Cited by 19
“We crossed ROR γ t flox mice ( 27 ) to tamoxifen-inducible CAGG- CRE-ER mice ( 28 ) to generate a strain where we can conditionally ablate ROR γ t expression in all cells and tissues.”
MethodAhmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Alshammari, M. A., & Attia, S. M. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.08.020 · Cited by 19
Transgenerational consequences of maternal immune activation
Pollak, D. D., & Weber‐Stadlbauer, U. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.06.006 · Cited by 20
Wang, H. V., Forestier, S., & Corces, V. G. (2021) · Biology of Reproduction · doi:10.1093/biolre/ioab097 · Cited by 19
“Viral infection during pregnancy is the best 16 known environmental risk factor to increase the frequency of autism in the offspring [4, 12, 13]; for example, 17 based on a large Swedish study with a sample size of 24,414 ASD cases, 3.”
BackgroundDelaney, S., & Hornig, M. (2018) · Current Environmental Health Reports · doi:10.1007/s40572-018-0186-z · Cited by 21
Akhtar, A., & Rahaman, S. B. (2025) · Brain Sciences · doi:10.3390/brainsci15080853 · Cited by 21
“In one notable study, Choi and collaborators (2016) demonstrated that the administration of neutralizing IL-17A monoclonal antibodies in pregnant mice exposed to MIA effectively prevented cortical malformations and limited the appearance of ASD-like behavior in the offspring [62].”
Shook, L. L., Castro, V. M., Ibanez-Pintor, L. C., Perlis, R. H., & Edlow, A. G. (2025) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000006112 · Cited by 18
In utero immune programming of autism spectrum disorder (ASD)
Jash, S., & Sharma, S. (2021) · Human Immunology · doi:10.1016/j.humimm.2021.02.002 · Cited by 18
Trifonova, E. A., Мустафин, З. С., Lashin, S. A., & Kochetov, A. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020967 · Cited by 19
“, interleukin-6), which, through the placenta, affects fetal brain development [13], blocking key pathways that prevent MIA-induced neurological and behavioral anomalies in ASD model systems [14].”
BackgroundMaternal and Adult Interleukin-17A Exposure and Autism Spectrum Disorder
Fujitani, M., Miyajima, H., Otani, Y., & Liu, X. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.836181 · Cited by 20
“5, resulting in an ASD-like phenotype, including abnormal behaviors in ultrasonic vocalization tests, social interaction tests, and marble burying tests (25).”
BackgroundInfluentialLiu, W., Li, L., Xia, X., Zhou, X., Du, Y., Yin, Z., & Wang, J. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.780747 · Cited by 18
“Maternal immune activation— especially involving interleukin (IL)-17—was found to be a major contributor to neurodevelopmental abnormalities in a mouse model of ASD (8).”
BackgroundNeuro-immune crosstalk in depressive symptoms of multiple sclerosis
Wang, C., Zhou, Y., & Feinstein, A. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106005 · Cited by 20
Physiological roles of human interleukin‐17 family
Liu, Y., Ouyang, Y., You, W., Liu, W., Cheng, Y., Mai, X., & Shen, Z. (2023) · Experimental Dermatology · doi:10.1111/exd.14964 · Cited by 22
Autism-associated synaptic mutations impact the gut-brain axis in mice
Lee, C. Y. Q., Franks, A. E., & Hill‐Yardin, E. L. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.072 · Cited by 18
Bagnall-Moreau, C., Huerta, P. T., Comoletti, D., Bella, A. L., Berlin, R., Zhao, C., Volpe, B. T., Diamond, B., & Brimberg, L. (2020) · Scientific Reports · doi:10.1038/s41598-020-71201-9 · Cited by 18
Arnold, M. L., & Saijo, K. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.717411 · Cited by 21
Bendix, I., Hadamitzky, M., Herz, J., & Felderhoff‐Müser, U. (2018) · Pediatric Research · doi:10.1038/s41390-018-0222-6 · Cited by 19
Toward a better understanding of T cell dysregulation in autism: An integrative review
Moreno, R. J., Amara, R. A., & Ashwood, P. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.10.009 · Cited by 18
“In a study by Choi and colleagues, MIA induction of dams lacking T cell specific RoR γ T resulted in reduced marble buying and increased social interactions in offspring (Choi, 2016).”
IL-1R1-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness
Yang, L., Andina, M., Witkowski, M., King, H. O., Wickersham, I. R., Huh, J. R., & Choi, G. B. (2025) · Cell · doi:10.1016/j.cell.2025.10.040 · Cited by 21
Self-citationDenucci, B. L., de Lima, L. S., Mota, I. F. L., Azevedo, J. R. M., Veras, L. G., Bicca, J. V. M. L., Santana, B. D. M., Pinheiro, G. B., Coelho, G. G., & Mortari, M. R. (2021) · Reproductive Toxicology · doi:10.1016/j.reprotox.2021.10.010 · Cited by 20
Immune synaptopathies: how maternal immune activation impacts synaptic function during development
Matteoli, M., Pozzi, D., Fossati, M., & Menna, E. (2023) · The EMBO Journal · doi:10.15252/embj.2023113796 · Cited by 18
“…also plays key roles in neurodevelopment: mouse embryos prenatally exposed to IL-6 display behavioral defects at adult stages (Smith et al , 2007; Choi et al , 2016), and elevated IL-6 during human pregnancy is linked with altered brain connectivity and defective working memory in human newborns…”
Neural cell-types and circuits linking thermoregulation and social behavior
Rogers, J. F., Vandendoren, M., Prather, J. F., Landen, J. G., Bedford, N. L., & Nelson, A. C. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105667 · Cited by 21
“However, a caveat to this interpretation is that inflammation is capable of changing several brain functions, including arousal (Swardfager et al., 2016) and social interaction (Choi et al., 2016).”
Manjeese, W., Mvubu, N. E., Steyn, A. J. C., & Mpofana, T. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18094513 · Cited by 14
“Recent findings indicate that IL-17A is a mediator of MIA that reduces social interaction and induces repetitive behaviors in MIA offspring [4,31], suggesting that the elevated plasma IL-17A levels in Mtb-induced MIA offspring most probably evoked repetitive behaviors and a lack of social skills in our study.”
BackgroundResultVistnes, M., Tapia, G., Mårild, K., Midttun, Ø., Ueland, P. M., Viken, M. K., Magnus, P. M., Berg, J. P., Gillespie, K. M., Skrivarhaug, T., et al. (2017) · American Journal of Reproductive Immunology · doi:10.1111/aji.12802 · Cited by 17
Liao, Y., Zhang, Y.-N., Liu, X.-L., Lu, Y., Zhang, L., Xi, T., Shu, S., & Feng, F. (2018) · Current Medical Science · doi:10.1007/s11596-018-1924-z · Cited by 17
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Alotaibi, M. R., Alasmari, A. F., Alshammari, M. A., Al‐Mazroua, H. A., & Attia, S. M. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.01.016 · Cited by 17
The Role of Gut Microbiota in the High-Risk Construct of Severe Mental Disorders: A Mini Review
Sani, G., Manchia, M., Simonetti, A., Janiri, D., Paribello, P., Pinna, F., & Carpiniello, B. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.585769 · Cited by 18
Zhang, Q., Li, Y., Zhang, J., Cui, Y., Sun, S., Chen, W., Shi, L., Zhang, Y., & Hou, Z. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.11.039 · Cited by 16
DeSpenza, T., Kiziltug, E., Allington, G., Barson, D. G., McGee, S., O’Connor, D. A., Robert, S. M., Mekbib, K. Y., Nanda, P., Greenberg, A. B. W., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-024-01865-3 · Cited by 17
“Increased frequency of ventriculomegaly has been reported in ASD 82–86 , including individuals with PTEN -mutant ASD and macrocephaly 87 .”
Immunity and neuroinflammation in early stages of life and epilepsy
García, A. V., López‐Meraz, M. L., González, M. I., Rocha, L., Peixoto-Santos, J. E., & Cavalheiro, É. A. (2025) · Epilepsia · doi:10.1111/epi.18361 · Cited by 17
“31,32 35 Moreover, T-cell density correlates with seizure frequency in several focal epilepsies, and T-cell response was linked to postsurgical seizure control in tuberous sclerosis.”
Zhang, W., Huang, C., Yao, H., Yang, S., Jiapaer, Z., Song, J., & Wang, X. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00471-y · Cited by 16
“Immune alterations, particularly maternal immune activation, may be involved in the pathophysiology of ASD [173, 174].”
Gomes, A. K. S., Dantas, R. M., Yokota-Moreno, B. Y., Silva, A. L. T. E., Griesi‐Oliveira, K., Passos‐Bueno, M. R., & Sertie, A. L. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.828646 · Cited by 15
“We also found that treatment of ASD- and control-derived NPCs with rhIL-17a had no effect on the expression of IL17RA, which may suggest that undifferentiated NPCs are not the cellular source of upregulated IL17RA expression observed in the brain upon MIA (Choi et al., 2016).”
BackgroundResultInfluentialGriego, E., Segura-Villalobos, D., Lamas, M., & Galván, E. J. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.07.005 · Cited by 16
Wong, R. S.-Y. (2022) · The Egyptian Journal of Neurology Psychiatry and Neurosurgery · doi:10.1186/s41983-022-00525-2 · Cited by 18
“However, maternal pre-treatment of IL-17a blocking antibodies inhibited IL-17a mRNA expression in the foetal brain, suggesting that upregulation of foetal brain IL-17a was mediated via maternal IL-17a pathway and that proinflammatory maternal IL-17a played a role in the pathogenesis of ASD in mice offspring [62].”
BackgroundOxytocin Receptor in Cerebellar Purkinje Cells Does Not Engage in Autism-Related Behaviors
Shen, L.-P., Li, W., Pei, L.-Z., Yin, J., Xie, S.-T., Li, H.-Z., Yan, C., Wang, J., Zhang, Q., Zhang, X., et al. (2022) · The Cerebellum · doi:10.1007/s12311-022-01466-5 · Cited by 16
“As reported previously [46], at the habituation stage,”
BackgroundSources and Translational Relevance of Heterogeneity in Maternal Immune Activation Models
Meyer, U. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_398 · Cited by 17
Unnisa, A., Greig, N. H., & Kamal, M. A. (2022) · Current Neuropharmacology · doi:10.2174/1570159x21666221221142743 · Cited by 17
“The various models for studying the neuroglial interactions are tabulated in Table 1 [20-31].”
Altered cytokine levels in the cerebrospinal fluid of adult patients with autism spectrum disorder
Runge, K., Fiebich, B. L., Kuzior, H., Rausch, J., Maier, S. J., Dersch, R. S., Nickel, K., Domschke, K., van Elst, L. T., & Endres, D. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.12.032 · Cited by 18
Greenwood, E. A., Cedars, M. I., Lindquist, K. J., Bishop, S. L., Kim, Y.-S., Kaing, A., Prahl, M. K., Gaw, S. L., Corley, J., Hoskin, E. K., et al. (2024) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/jamapediatrics.2023.5743 · Cited by 19
Neuroimmune mechanisms in autism etiology - untangling a complex problem using human cellular models
Vacharasin, J. M., Ward, J. A., McCord, M. M., Cox, K., Imitola, J., & Lizarraga, S. B. (2024) · Oxford Open Neuroscience · doi:10.1093/oons/kvae003 · Cited by 17
“Moreover, inactivation of the IL-17RA either by antibody injection or using conditional genetics was sufficient to rescue MIA induced ASD-like behaviors [7, 133].”
InfluentialShen, C., Zhu, X., Chang, H., Li, C., Hou, M., Chen, L., Chen, L., Zhou, Z., Ji, M., & Xu, Z. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114787 · Cited by 17
IL-17A mediates a path to autism
Kugelberg, E. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.35 · Cited by 16
The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis
Donaldson, D. S., & Mabbott, N. A. (2016) · Journal of General Virology · doi:10.1099/jgv.0.000507 · Cited by 17
Transgenerational transmission of maternal stimulatory experience in domesticated birds
Liu, L., Yang, N., Xu, G., Liu, S., Wang, D., Song, J., Duan, Z., Yang, S., & Yu, Y. (2018) · The FASEB Journal · doi:10.1096/fj.201800762rr · Cited by 16
“To investigate,weused the viral analogpolyriboinosinic: polyribocytidylic [poly (I:C)] acid and the bacterial endotoxin LPS (11, 12) to treat the F0 hens and then investigated the effects and molecular mechanisms of immune stimulants across 3 generations in a chicken model.”
BackgroundOutside-in: Rethinking the etiology of autism spectrum disorders
Orefice, L. L. (2019) · Science · doi:10.1126/science.aaz3880 · Cited by 16
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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