Inflammatory macrophage phenotype in BTBR T+tf/J mice

Onore, Charity E.; Careaga, Milo; Babineau, Brooke A.; Schwartzer, Jared J.; Berman, Robert F.; Ashwood, Paul

doi:10.3389/fnins.2013.00158

Cited by 77Autism Spectrum Disorder ResearchNeuroinflammation and Neurodegeneration MechanismsTryptophan and brain disorders

Inflammatory macrophage phenotype in BTBR T+tf/J mice

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Onore, Charity E., Careaga, Milo, Babineau, Brooke A., Schwartzer, Jared J., Berman, Robert F., Ashwood, Paul·2013·Frontiers in Neuroscience

DOI 10.3389/fnins.2013.00158PMC PMC3774991

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Abstract

Although autism is a behaviorally defined disorder, many studies report an association with increased pro-inflammatory cytokine production. Recent characterization of the BTBR T+tf/J (BTBR) inbred mouse strain has revealed several behavioral characteristics including social deficits, repetitive behavior, and atypical vocalizations which may be relevant to autism. We therefore hypothesized that, asocial BTBR mice, which exhibit autism-like behaviors, may have an inflammatory immune profile similar to that observed in children with autism. The objectives of this study were to characterize the myeloid immune profile of BTBR mice and to explore their associations with autism-relevant behaviors. C57BL/6J (C57) mice and BTBR mice were tested for social interest and repetitive self-grooming behavior. Cytokine production was measured in bone-marrow derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFNγ/LPS to ascertain any M1/M2 skewing. After LPS stimulation, BTBR macrophages produced higher levels of IL-6, MCP-1, and MIP-1α and lower IL-10 (p < 0.01) than C57 mice, suggesting an exaggerated inflammatory profile. After exposure to IL-4/LPS BTBR macrophages produced less IL-10 (p < 0.01) than C57 macrophages and more IL-12p40 (p < 0.01) suggesting poor M2 polarization. Levels of IL-12(p70) (p < 0.05) were higher in BTBR macrophages after IFNγ/LPS stimulation, suggesting enhanced M1 polarization. We further observed a positive correlation between grooming frequency, and production of IL-12(p40), IL-12p70, IL-6, and TNFα (p < 0.05) after treatment with IFNγ/LPS across both strains. Collectively, these data suggest that the asocial BTBR mouse strain exhibits a more inflammatory, or M1, macrophage profile in comparison to the social C57 strain. We have further demonstrated a relationship between this relative increase in inflammation and repetitive grooming behavior, which may have relevance to repetitive and stereotyped behavior of autism.

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The BTBR mouse has been shown to display a pro-inflammatory phenotype that is thought to contribute to the development of ASD-like behavior.
“Indeed, the BTBR mouse has been shown to display a pro-inflammatory phenotype that is thought to contribute to the development of ASD-like behavior (Careaga et al., 2015; Heo et al., 2011; Onore et al., 2013).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Onore et al., 2013

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Background
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“Mice were scored for spontaneous self-grooming behaviors as described previously (Yang et al., 2007, 2009; McFarlane et al., 2008; Silverman et al., 2010).”
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Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice
Carlezon, W. A., Kim, W., Missig, G., Finger, B. C., Landino, S. M., Alexander, A. J., Mokler, E. L., Robbins, J. O., Li, Y., Bolshakov, V. Y., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-53294-z · Cited by 143 · see citing works
Immune Abnormalities in Autism Spectrum Disorder—Could They Hold Promise for Causative Treatment?
Gładysz, D., Krzywdzińska, A., & Hozyasz, K. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0822-x · Cited by 130 · see citing works
Bridging autism spectrum disorders and schizophrenia through inflammation and biomarkers – pre-clinical and clinical investigations
Prata, J., Santos, S. G., Almeida, M. I., Coelho, R., & Barbosa, M. A. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0938-y · Cited by 115 · see citing works
Palmitoylethanolamide counteracts autistic-like behaviours in BTBR T+tf/J mice: Contribution of central and peripheral mechanisms
Cristiano, C., Pirozzi, C., Coretti, L., Cavaliere, G., Lama, A., Russo, R., Lembo, F., Mollica, M. P., Meli, R., Calignano, A., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.09.003 · Cited by 96 · see citing works
“BTBR mice showed a phenotype that mirror many ASD pathological aspects found in children patients, including alterations in both innate and adaptive arms of the immune system (Onore et al., 2013).”
Cerebellar Oxidative DNA Damage and Altered DNA Methylation in the BTBR T+tf/J Mouse Model of Autism and Similarities with Human Post Mortem Cerebellum
Shpyleva, S., Ivanovsky, S., de Conti, A., Melnyk, S., Tryndyak, V., Beland, F. A., James, S. J., & Pogribny, I. P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113712 · Cited by 83 · see citing works
The role of marine omega-3 in human neurodevelopment, including Autism Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder – a review
Martins, B., Bandarra, N. M., & Figueiredo‐Braga, M. (2019) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2019.1573800 · Cited by 86 · see citing works
Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics
Islamuddin, M., & Qin, X.-B. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01996-3 · Cited by 81 · see citing works
“This M1 polarization is characterized by the elevated levels of proin ﬂ ammatory cytokines such as IL-6, IL-1, IL-23, IL-12, matrix metalloproteinase 12 (MMP12), iNOS and MINCLE [40 – 43].”
Background
Inflammatory profiles in the BTBR mouse: how relevant are they to autism spectrum disorders?
Careaga, M., Schwartzer, J., & Ashwood, P. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.006 · Cited by 77 · see citing works
Increased oxidative stress in the cerebellum and peripheral immune cells leads to exaggerated autism-like repetitive behavior due to deficiency of antioxidant response in BTBR T + tf/J mice
Nadeem, A., Ahmad, S. F., Al-Harbi, N. O., Attia, S. M., Alshammari, M. A., Alzahrani, K. S., & Bakheet, S. A. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.09.012 · Cited by 65 · see citing works
“Several previous reports have shown that BTBR mice exhibit peripheral and CNS abnormalities which are similar to the patients of autism (Careaga et al., 2015; Onore et al., 2013; Nadeem et al., 2017a; 2017b; Bjorklund et al., 2016).”
Role of the Gut Microbiota in the Pathophysiology of Autism Spectrum Disorder: Clinical and Preclinical Evidence
Roussin, L., Prince, N., Perez‐Pardo, P., Kraneveld, A. D., Rabot, S., & Naudon, L. (2020) · Microorganisms · doi:10.3390/microorganisms8091369 · Cited by 64 · see citing works
Systemic maternal inflammation promotes ASD via IL-6 and IFN-γ
Majerczyk, D., Ayad, E., Brewton, K. L., Saing, P., & Hart, P. C. (2022) · Bioscience Reports · doi:10.1042/bsr20220713 · Cited by 62 · see citing works
p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse
Robson, M. J., Quinlan, M. A., Margolis, K. G., Gajewski-Kurdziel, P. A., Veenstra-VanderWeele, J. M., Gershon, M. D., Watterson, D. M., & Blakely, R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1809137115 · Cited by 57 · see citing works
Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder
van de Wouw, M., Walsh, C. J., Vigano, G. M. D., Lyte, J. M., Boehme, M., Gual‐Grau, A., Crispie, F., Walsh, A. M., Clarke, G. A., Dinan, T. G., et al. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.07.004 · Cited by 52 · see citing works
“Similarly, macrophages derived from BTBR mice secrete more inflammatory cytokines, which correlates with their ASD-associated behavioural phenotype (Onore et al. 2013).”
Systemic inflammation in asocial BTBR T + tf/J mice predisposes them to increased psoriatic inflammation
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 53 · see citing works
Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy
Long, H., Lichtnekert, J., Andrassy, J., Schraml, B. U., Romagnani, P., & Anders, H.-J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1194988 · Cited by 46 · see citing works
Metformin Administration During Early Postnatal Life Rescues Autistic-Like Behaviors in the BTBR T+ Itpr3tf/J Mouse Model of Autism
Wang, L. Y., Cai, Y., & Fan, X. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00290 · Cited by 47 · see citing works
Non-diagnostic symptoms in a mouse model of autism in relation to neuroanatomy: the BTBR strain reinvestigated
Faraji, J., Karimi, M., Lawrence, C., Mohajerani, M. H., & Metz, G. A. S. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0280-x · Cited by 46 · see citing works
Dysregulated gene expression associated with inflammatory and translation pathways in activated monocytes from children with autism spectrum disorder
Hughes, H. K., Rowland, M. E., Onore, C. E., Rogers, S. J., Ciernia, A. V., & Ashwood, P. (2022) · Translational Psychiatry · doi:10.1038/s41398-021-01766-0 · Cited by 49 · see citing works
“Macrophage activation was also present in ASD-relevant mouse models, with enhanced production of inflammatory cytokines correlating with severity of behaviors including increased grooming and decreased social approach [34, 35].”
Background
Potential crosstalk between sonic hedgehog‐WNT signaling and neurovascular molecules: Implications for blood–brain barrier integrity in autism spectrum disorder
Gozal, E., Jagadapillai, R., Cai, J., & Barnes, G. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15460 · Cited by 45 · see citing works
Effect of social odor context on the emission of isolation-induced ultrasonic vocalizations in the BTBR T+tf/J mouse model for autism
Wöhr, M. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00073 · Cited by 43 · see citing works
Exposure to the plasticizer, Di-(2-ethylhexyl) phthalate during juvenile period exacerbates autism-like behavior in adult BTBR T + tf/J mice due to DNA hypomethylation and enhanced inflammation in brain and systemic immune cells
Nadeem, A., Al-Harbi, N. O., Ahmad, S. F., Alhazzani, K., Attia, S. M., Alsanea, S., Alhoshani, A., Mahmood, H. M., Alfardan, A. S., & Bakheet, S. A. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110249 · Cited by 43 · see citing works
Activation of adenosine A2A receptor signaling regulates the expression of cytokines associated with immunologic dysfunction in BTBR T + Itpr3 tf /J mice
Ansari, M. A., Attia, S. M., Nadeem, A., Bakheet, S. A., Raish, M., Khan, T. H., Al‐Shabanah, O. A., & Ahmad, S. F. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.04.012 · Cited by 41 · see citing works
“These elevations in immune markers are associated with the severity of social impairments and repetitive grooming behaviors (Heo et al., 2011; Onore et al., 2013).”
Microglia-derived neuregulin expression in psychiatric disorders
Ikawa, D., Makinodan, M., Iwata, K., Ohgidani, M., Kato, T. A., Yamashita, Y., Yamamuro, K., Kimoto, S., Toritsuka, M., Yamauchi, T., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.01.003 · Cited by 39 · see citing works
“Such studies have reported abnormal cytokine profiles, reduced lymphocyte numbers, weakened T-cell mitogen responses, imbalanced serum immunoglobulin levels, and aberrant autoimmune-related gene expression in these patients (Ashwood et al., 2006; Estes and McAllister, 2015; Hughes et al., 2016; Muller et al., 2015; On…”
Background
S3I-201, a selective Stat3 inhibitor, restores neuroimmune function through upregulation of Treg signaling in autistic BTBR T+ Itpr3tf/J mice
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Alshammari, M. A., Khan, M. R., Alsaad, A. M. S., & Attia, S. M. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.09.006 · Cited by 37 · see citing works
High expression of Endogenous Retroviruses from intrauterine life to adulthood in two mouse models of Autism Spectrum Disorders
Cipriani, C., Ricceri, L., Matteucci, C., Felice, A. D., Tartaglione, A. M., Argaw-Denboba, A., Pica, F., Grelli, S., Calamandrei, G., Vallebona, P. S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-017-19035-w · Cited by 34 · see citing works
Comparative Gene Expression Analysis of Two Mouse Models of Autism: Transcriptome Profiling of the BTBR and En2−/− Hippocampus
Provenzano, G., Corradi, Z., Monsorno, K., Fedrizzi, T., Ricceri, L., Scattoni, M. L., & Bozzi, Y. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00396 · Cited by 34 · see citing works
C57BL/6J bone marrow transplant increases sociability in BTBR T+ Itpr3tf/J mice
Schwartzer, J. J., Onore, C. E., Rose, D. R., & Ashwood, P. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.05.019 · Cited by 34 · see citing works
“This neuro-immune association is evident in the BTBR mouse model, an inbred strain characterized by both elevated pro-inflammatory signaling and reduced social interactions (Careaga et al., 2015b; McFarlane et al., 2008; Onore et al., 2013).”
BackgroundInfluential
Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability
Lewis, M. L., Kesler, M., Candy, S., Rho, J. M., & Pittman, Q. J. (2018) · Epilepsia · doi:10.1111/epi.14440 · Cited by 31 · see citing works
The histamine H3R and dopamine D2R/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf/J mice by multiple actions
Venkatachalam, K., Eissa, N., Awad, M. A., Jayaprakash, P., Zhong, S., Stölting, F., Stark, H., & Sadek, B. S. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111517 · Cited by 29 · see citing works
Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism
Cristiano, C., Volpicelli, F., Crispino, M., Lacivita, E., Russo, R., Leopoldo, M., Calignano, A., & Perrone‐Capano, C. (2022) · Pharmaceuticals · doi:10.3390/ph15020161 · Cited by 29 · see citing works
“Furthermore, BTBR mice have dysfunction of both the innate and adaptive responses of the immune system, and an inflammatory immune profile resembling ASD [24].”
Background
Lead (Pb) exposure exacerbates behavioral and immune abnormalities by upregulating Th17 and NF-κB-related signaling in BTBR T+ Itpr3tf/J autistic mouse model
Almutairi, 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 · see citing works
Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring
Hreha, T. N., Collins, C. A., Daugherty, A. L., Griffith, J. M., Hruska, K. A., & Hunstad, D. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01641 · Cited by 25 · see citing works
Strain differences in behaviour and immunity in aged mice: Relevance to Autism
O’Connor, R., van de Wouw, M., Moloney, G. M., Ventura‐Silva, A. P., O’Riordan, K. J., Golubeva, A. V., Dinan, T. G., Schellekens, H., & Cryan, J. F. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113020 · Cited by 25 · see citing works
Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4+ T cells from a BTBR T+ Itpr3tf/J mouse model of autism
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Almutairi, M. M., & Attia, S. M. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.08.002 · Cited by 25 · see citing works
“Neuroimmune dysregulations are noticeable in BTBR mice, including abnormal behavior symptoms and altered inflammatory mediators (Onore et al., 2013).”
Characterization of the biochemical and behavioral effects of cannabidiol: implications for migraine
Greco, R., Francavilla, M., Demartini, C., Zanaboni, A. M., Sodergren, M. H., Facchetti, S., Pacchetti, B., Palmisani, M., Franco, V., & Tassorelli, C. (2023) · The Journal of Headache and Pain · doi:10.1186/s10194-023-01589-y · Cited by 25 · see citing works
“In agreement, it was reported that the asocial BTBR mouse strain show an inflammatory profile, such as connections between inflammation and M1-related cytokines associated with repetitive grooming activity [49].”
Background
Brain Autoantibodies in Autism Spectrum Disorder
Elamin, N. E., & AL-Ayadhi, L. Y. (2014) · Biomarkers in Medicine · doi:10.2217/bmm.14.1 · Cited by 24 · see citing works
Development, phenotypes of immune cells in BTBR TItpr3/J mice
Uddin, M. N., Yao, Y., MANLEY, K. M., & Lawrence, D. A. (2020) · Cellular Immunology · doi:10.1016/j.cellimm.2020.104223 · Cited by 21 · see citing works
5-Aminoisoquinolinone, a PARP-1 Inhibitor, Ameliorates Immune Abnormalities through Upregulation of Anti-Inflammatory and Downregulation of Inflammatory Parameters in T Cells of BTBR Mouse Model of Autism
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 · see citing works
“C57BL/6 (C57) mice displayed higher levels of sociability and are frequently used as a comparative strain against BTBR mice [37,38].”
Background
Beneficial Effects of Fingolimod on Social Interaction, CNS and Peripheral Immune Response in the BTBR Mouse Model of Autism
Simone, R. D., Butera, A., Armida, M., Pèzzola, A., Boirivant, M., Potenza, R. L., & Ricceri, L. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.03.041 · Cited by 22 · see citing works
ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5
Strekalova, T. V., Svirin, E. P., Veniaminova, E. A., Kopeikina, E., Veremeyko, T., Yung, A. W. Y., Proshin, A. T., Walitza, S., Anthony, D. C., Lim, L. W., et al. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100306 · Cited by 22 · see citing works
“…IL-6 and TNF in mutants and LPS-induced systemic inflammation is reminiscent of a ‘double hit’ phenomenon (Carlezon et al., 2019; Couch et al, 2013, 2016; Onore et al., 2013; Yasumatsu et al., 2020) and could explain the exacerbation of the changes in social behavior observed in the St3gal5 / mice.”
BackgroundResult
Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity
Jagadapillai, R., Qiu, X., Ojha, K., Li, Z., El-Baz, A. S., Zou, S., Gozal, E., & Barnes, G. N. (2022) · Cells · doi:10.3390/cells11142211 · Cited by 21 · see citing works
“Several studies have attempted to link neuroinflammation and microglial changes with pathophysiological characteristics of mouse models of brain disease [89,92].”
Background
Protection by tyrosine kinase inhibitor, tyrphostin AG126, through the suppression of IL-17A, RORγt, and T-bet signaling, in the BTBR mouse model of autism
Ahmad, 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 · see citing works
Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Mohammad, R., & Attia, S. M. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0548-9 · Cited by 19 · see citing works
“The neuroimmune relation in the BTBR mice is characterized by higher pro-inflammatory signaling and diminished social interactions [52, 53].”
Background
A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model
Lin, C.-W., Septyaningtrias, D. E., Chao, H., Konda, M., Atarashi, K., Takeshita, K., Tamada, K., Nomura, J., Sasagawa, Y., Tanaka, K. Y., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01566-y · Cited by 17 · see citing works
“RESULTS Single-cell RNA-seq analysis of AGM hemogenic endothelial cells identifies HDAC1 as the pathogenic factor for immune dysregulation Previous work has identified phenotypes of immune dysfunction in the BTBR idiopathic autism model, including both inflammatory and immune suppression across multiple immune cell ty…”
Background
Disruption of visual circuit formation and refinement in a mouse model of autism
Cheng, N., Khanbabaei, M., Murari, K., & Rho, J. M. (2016) · Autism Research · doi:10.1002/aur.1687 · Cited by 16 · see citing works
“As an exaggerated inflammatory profile has been observed in the BTBR animals [Heo, Zhang, Gao, Miller, & Lawrence, 2011; Onore et al., 2013], it would be of interest to test whether altered immune signalling in the BTBR animals underlies the impairment reported here.”
Background
Microglia-triggered hypoexcitability plasticity of pyramidal neurons in the rat medial prefrontal cortex
Yamawaki, Y., Wada, Y., Matsui, S., & Ohtsuki, G. (2022) · Current Research in Neurobiology · doi:10.1016/j.crneur.2022.100028 · Cited by 16 · see citing works
CXCR2 antagonist SB332235 mitigates deficits in social behavior and dysregulation of Th1/Th22 and T regulatory cell-related transcription factor signaling in male BTBR T+ Itpr3tf/J mouse model of autism
Albekairi, N. A., Nadeem, A., Ansari, M. A., Attia, S. M., Bakheet, S. A., Alanazi, M. M., Alhamed, A. S., Albekairi, T. H., Al‐Mazroua, H. A., Ibrahim, K. E., et al. (2022) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173408 · Cited by 14 · see citing works
Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism
Gong, H., Yao, L., Deng, S., Lv, K., Luo, J., Luo, Y., Du, Z., Wu, L.-F., Liu, T., Wang, X., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107568 · Cited by 14 · see citing works
Gestational hypothyroxinemia induces ASD-like phenotypes in behavior, proinflammatory markers, and glutamatergic protein expression in mouse offspring of both sexes
González-Madrid, E., Rangel-Ramírez, M. A., Opazo, M. C., Méndez, L., Böhmwald, K., Bueno, S. M., González, P. A., Kalergis, A. M., & Riedel, C. A. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1381180 · Cited by 14 · see citing works
“Given that M1-like macrophages exhibit a pro-in ﬂ ammatory pro ﬁ le (103), this imbalance agrees with the notion of an underlying basal in ﬂ ammatory state in HTX-offspring.”
Brain-immune interactions in health and disease
Dénes, Á., & Miyan, J. A. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00382 · Cited by 12 · see citing works
“Paul Ashwood and colleagues report that the behavioral characteristics, including social deficits, repetitive grooming behavior and atypical vocalizations, observed in BTBR T+tf/J mice are associated with the development of an inflammatory macrophage phenotype in this strain (Onore et al., 2013).”
Background
Methylmercury chloride exposure exacerbates existing neurobehavioral and immune dysfunctions in the BTBR T+ Itpr3tf/J mouse model of autism
Al‐Mazroua, H. A., Nadeem, A., Ansari, M. A., Attia, S. M., Albekairi, T. H., Bakheet, S. A., Alobaidi, A. F., Alhosaini, K. A., Alqarni, S. A., Ibrahim, K. E., et al. (2022) · Immunology Letters · doi:10.1016/j.imlet.2022.03.001 · Cited by 11 · see citing works
Social deficits in BTBR T+ Itpr3tf/J mice vary with ecological validity of the test
Winiarski, M. J., Kondrakiewicz, L., Kondrakiewicz, K., Jędrzejewska‐Szmek, J., Turzyński, K., Knapska, E., & Meyza, K. Z. (2022) · Genes Brain & Behavior · doi:10.1111/gbb.12814 · Cited by 10 · see citing works
Potential Neuroprotective Effect of Melatonin in the Hippocampus of Male BTBR Mice
Bonetti, M., Giugno, L., Borsani, E., & Bonomini, F. (2024) · Nutrients · doi:10.3390/nu16111652 · Cited by 10 · see citing works
“Moreover, the BTBR mouse strain shares with most ASD patients an enhanced oxidative stress and inflammatory state in both peripheral tissues [31,32] and the CNS [33,34].”
Background
A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms
Segawa, K., Blumenthal, Y., Yamawaki, Y., & Ohtsuki, G. (2021) · Biology · doi:10.3390/biology10010034 · Cited by 11 · see citing works
“A recent study showed the behavioral anomaly of MIA offspring is dependent on the IL-17a pathway [205].”
Background
On the Potential Therapeutic Roles of Taurine in Autism Spectrum Disorder
Rubio‐Casillas, A., Redwan, E. M. M. M., & Uversky, V. N. (2022) · Neuroglia · doi:10.3390/neuroglia4010001 · Cited by 10 · see citing works
“There is also proof that most of these abnormal immunological patterns are linked to the worsening of autistic behavior [14].”
Background
Seizure susceptibility to various convulsant stimuli in the BTBR mouse model of autism spectrum disorders
Tallarico, M., Leo, A., Russo, E., Citraro, R., Palma, E., & Sarro, G. D. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1155729 · Cited by 9 · see citing works
“BTBR mice also exhibit dysregulation of both the innate and adaptive systems and an inflammatory immune profile resembling ASD (Onore et al., 2013).”
Background
Alleviation of Autophagic Deficits and Neuroinflammation by Histamine H3 Receptor Antagonist E159 Ameliorates Autism-Related Behaviors in BTBR Mice
Thomas, S. D., Jayaprakash, P., Marwan, N. Z. H. J., Aziz, E. A. B. A., Kuder, K., Łażewska, D., Kieć‐Kononowicz, K., & Sadek, B. S. (2024) · Pharmaceuticals · doi:10.3390/ph17101293 · Cited by 8 · see citing works
Genetic variants drive altered epigenetic regulation of endotoxin response in BTBR macrophages
Ciernia, A. V., Link, V. M., Careaga, M., LaSalle, J. M., & Ashwood, P. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.058 · Cited by 8 · see citing works
The Exposure to Lead (Pb) Exacerbates Immunological Abnormalities in BTBR T+ Itpr3tf/J Mice through the Regulation of Signaling Pathways Relevant to T Cells
Assiri, M. A., Albekairi, T. H., Ansari, M. A., Nadeem, A., Attia, S. M., Bakheet, S. A., Shahid, M., Aldossari, A. A., Almutairi, M. M., Almanaa, T. N., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216218 · Cited by 8 · see citing works
Aflatoxin B1 Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T+Itpr3tf/J Mouse Model of Autism
Alwetaid, M. Y., Almanaa, T. N., Bakheet, S. A., Ansari, M. A., Nadeem, A., Attia, S. M., Hussein, M. H., & Ahmad, S. F. (2023) · Brain Sciences · doi:10.3390/brainsci13111519 · Cited by 7 · see citing works
Neuroinflammation in Animal Models of Autism
Kazlauskas, N., Robinson‐Agramonte, M. D. L. Á., & Depino, A. M. (2015) · Springer eBooks · doi:10.1007/978-3-319-16321-5_8 · Cited by 7 · see citing works
Deficit in Social Relationships and Reduced Field of Interest in Mice
Roubertoux, P. L., Carlier, M., & Tordjman, S. (2014) · Neuromethods · doi:10.1007/978-1-4939-2250-5_14 · Cited by 5 · see citing works
The Role of Inflammation in Autism Spectrum Disorder
Ferretti, C. J., & Hollander, E. (2015) · Current topics in neurotoxicity · doi:10.1007/978-3-319-13602-8_14 · Cited by 5 · see citing works
Neuroinflammation and autism: what have we learned so far?
Aytulun, A., & Ünal, D. (2024) · International Journal of Developmental Disabilities · doi:10.1080/20473869.2024.2366722 · Cited by 4 · see citing works
“In efforts to unravel the mechanisms driving autism-like behaviors in BTBR mice, in vitro studies utilizing macrophages obtained from these mice have shown an increase in the M1 phenotype when exposed to both proinflammatory and anti-inflammatory cytokines (Onore et al. 2013).”
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doi: 10.3389/fnins.2013.00158 Inflammatory macrophage phenotype in BTBR T tf/J mice+
Onore, C. E., Careaga, M., Babineau, B. A., Schwartzer, J. J., Berman, R. F., & Ashwood, P. (2013)
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Unique Features of the Immune Response in BTBR Mice
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Evaluation of Mucosal Immunity in BTBR T+tf/J Mice Resembling Autism Spectrum Disorder
Hwang, S. R., Jo, J. H., Shin, K. M., Jang, Y. Y., Kim, J. Y., Yeo, K. U., Kim, H. A., & Heo, Y. (2012) · Korean Journal of Environmental Health Sciences · doi:10.5668/jehs.2012.38.6.541 · Cited by 1 · see citing works

Authors: Onore, C. E., Careaga, M., Babineau, B. A., Schwartzer, J. J., Berman, R. F., & Ashwood, P.
Affiliations: University of California, Davis (US)
University of California, San Francisco (US)
Corresponding author: Ashwood, Paul
ORCID: Careaga, Milo
Schwartzer, Jared J.
Berman, Robert F.
Ashwood, Paul
Venue: Frontiers in Neuroscience
Publisher: Frontiers Media SA
Published: 2013
Volume: 7
Pages: 158-158
ISSN: 1662-453X (ISSN-L)
DOI: 10.3389/fnins.2013.00158
PMC: PMC3774991
OpenAlex: W1966784044
Cited by: 77
References: 54
Citations by year: 2024: 6 · 2023: 7 · 2022: 12 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 11 · 2017: 9 · 2016: 3 · 2015: 3 · 2014: 8
FWCI: 2.56
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Frontiers in Neuroscience (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
eScholarship (California Digital Library) (submittedVersion)
Funders: Emch Foundation
National Alliance for Research on Schizophrenia and Depression
National Institutes of Health
National Institute of Mental Health (T32MH073124)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: BTBR T+tf/J mice, autism spectrum disorder, macrophage polarization, M1/M2 macrophages, neuroinflammation, social dysfunction, inflammatory cytokines, IL-12, interleukin-6, IL-10, autism-like behavior

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