Abstract
Oxidative stress including decreased antioxidant enzyme activities, elevated lipid peroxidation, and accumulation of advanced glycation end products in the blood from children with autism spectrum disorders (ASD) has been reported. The mechanisms affecting the development of ASD remain unclear; however, toxic environmental exposures leading to oxidative stress have been proposed to play a significant role. The BTBRT+Itpr3tf/J (BTBR) strain provides a model to investigate the markers of oxidation in a mouse strain exhibiting ASD-like behavioral phenotypes. In the present study, we investigated the level of oxidative stress and its effects on immune cell populations, specifically oxidative stress affecting surface thiols (R-SH), intracellular glutathione (iGSH), and expression of brain biomarkers that may contribute to the development of the ASD-like phenotypes that have been observed and reported in BTBR mice. Lower levels of cell surface R-SH were detected on multiple immune cell subpopulations from blood, spleens, and lymph nodes and for sera R-SH levels of BTBR mice compared to C57BL/6 J (B6) mice. The iGSH levels of immune cell populations were also lower in the BTBR mice. Elevated protein expression of GATA3, TGM2, AhR, EPHX2, TSLP, PTEN, IRE1α, GDF15, and metallothionein in BTBR mice is supportive of an increased level of oxidative stress in BTBR mice and may underpin the pro-inflammatory immune state that has been reported in the BTBR strain. Results of a decreased antioxidant system suggest an important oxidative stress role in the development of the BTBR ASD-like phenotype.
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Abbreviations
- Ab:
-
Antibody
- AFM:
-
Alexa Fluor™ 488 C5 Maleimide
- ASD:
-
Autism spectrum disorders
- AhR:
-
Aryl hydrocarbon receptor
- B6:
-
C57BL/6 J
- CNS:
-
Central nervous system
- GSSG:
-
Glutathione disulfide
- iGSH:
-
Intracellular glutathione
- GMFI:
-
Geometric mean fluorescent intensity
- MT:
-
Metallothionein
- R-SH:
-
Thiol
- PTEN:
-
Phosphatase and tensin homolog
- TGM2:
-
Transglutaminase 2
- IRE1α:
-
Inositol-requiring enzyme 1alpha
- GDF15:
-
Growth differentiation factor 15
- EPHX2:
-
Epoxide hydrolases
- TSLP:
-
Thymic stromal lymphopoietin
- XRE:
-
Xenobiotic-responsive element
References
Adela R, Banerjee SK (2015) GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res 2015:490842. https://doi.org/10.1155/2015/490842
Ahmad SF, Zoheir KMA, Ansari MA, Nadeem A, Bakheet SA, Al-Ayadhi LY, Alzahrani MZ, Al-Shabanah OA, Al-Harbi MM, Attia SM (2017) Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. Mol Neurobiol 54(6):4390–4400. https://doi.org/10.1007/s12035-016-9977-0
Ahn Y, Sabouny R, Villa BR, Yee NC, Mychasiuk R, Uddin GM, Rho JM, Shutt TE (2020) Aberrant mitochondrial morphology and function in the BTBR mouse model of autism is improved by Two weeks of ketogenic diet. Int J Mol Sci 21(9):3266. https://doi.org/10.3390/ijms21093266
Akahoshi E, Yoshimura S, Ishihara-Sugano M (2006) Over-expression of AhR (aryl hydrocarbon receptor) induces neural differentiation of Neuro2a cells: neurotoxicology study. Environ Health 5:24. https://doi.org/10.1186/1476-069X-5-24
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J (2011) Altered T cell responses in children with autism. Brain Behav Immun 25(5)840-849. https://doi.org/10.1016/j.bbi.2010.09.002
Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C (2010) Vitamin D: modulator of the immune system. Curr Opin Pharmacol 10(4):482–496. https://doi.org/10.1016/j.coph.2010.04.001
Bhandari S (1989) “The chemotactic role of metallothionein in the extracellular environment” (2018). Doctoral Dissertations. https://opencommons.uconn.edu/dissertations/1989
Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5(1):9–19. https://doi.org/10.1097/WOX.0b013e3182439613
Bjørklund G, Tinkov AA, Hosnedlová B, Kizek R, Ajsuvakova OP, Chirumbolo S, Skalnaya MG, Peana M, Dadar M, El-Ansary A, Qasem H, Adams JB, Aaseth J, Skalny AV (2020) The role of glutathione redox imbalance in autism spectrum disorder: a review. Free Radic Biol Med 160:149–162. https://doi.org/10.1016/j.freeradbiomed.2020.07.017
Bjorklund G, Saad K, Chirumbolo S, Kern JK, Geier DA, Geier MR, Urbina MA (2016) Immune dysfunction and neuroinflammation in autism spectrum disorder. Acta Neurobiol Exp (Wars) 76(4):257–268. https://doi.org/10.21307/ane-2017-025
Careaga M, Schwartzer J, Ashwood P (2015) Inflammatory profiles in the BTBR mouse: how relevant are they to autism spectrum disorders? Brain Behav Immun 43:11–16. https://doi.org/10.1016/j.bbi.2014.06.006
Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cerebral Blood Flow Metabolism 21(1):2–14. https://doi.org/10.1097/00004647-200101000-00002
Charles N, Hardwick D, Daugas E, Illei GG, Rivera J (2010) Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat Med 16(6):701–707. https://doi.org/10.1038/nm.2159
Chauhan A, Audhya T, Chauhan V (2012) Brain region-specific glutathione redox imbalance in autism. Neurochem Res 37(8):1681–1689. https://doi.org/10.1007/s11064-012-0775-4
Chen GY, Nuñez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10(12):826–837. https://doi.org/10.1038/nri2873
Chen L, Shi XJ, Liu H, Mao X, Gui LN, Wang H, Cheng Y (2021) Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109). Transl Psychiatry 11(1):15. https://doi.org/10.1038/s41398-020-01135-3
Chiurchiù V, Maccarrone M (2011) Chronic inflammatory disorders and their redox control: from molecular mechanisms to therapeutic opportunities. Antioxidant Redox Signal 15(9):2605–2641. https://doi.org/10.1089/ars.2010.3547
Chu B, Li M, Cao X, Li R, Jin S, Yang H, Xu L, Wang P, Bi J (2021) IRE1α-XBP1 Affects the mitochondrial function of Aβ25–35-treated SH-SY5Y cells by regulating mitochondria-associated endoplasmic reticulum membranes. Front Cell Neurosci 15:614556. https://doi.org/10.3389/fncel.2021.614556
Crider A, Davis T, Ahmed AO, Mei L, Pillai A (2018) Transglutaminase 2 induces deficits in social behavior in mice. Neural Plast 2018:2019091. https://doi.org/10.1155/2018/2019091
Daglas M, Draxler DF, Ho H, McCutcheon F, Galle A, Au AE, Larsson P, Gregory J, Alderuccio F, Sashindranath M, Medcalf RL (2019) Activated CD8+ T cells cause long-term neurological impairment after traumatic brain injury in mice. Cell Rep 29(5):1178-1191.e6. https://doi.org/10.1016/j.celrep.2019.09.046
Dai H, Wang L, Li L, Huang Z, Ye L (2021) Metallothionein 1: a new spotlight on inflammatory diseases. Front Immunol 12:739918. https://doi.org/10.3389/fimmu.2021.739918
Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A (2003) Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol 53(4):533–537. https://doi.org/10.1002/ana.10557
Deponte M (2017) The incomplete glutathione puzzle: just guessing at numbers and figures? Antioxid Redox Signal 27(15):1130–1161. https://doi.org/10.1089/ars.2017.7123
Dong D, Zielke HR, Yeh D, Yang P (2018) Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. Autism Res 11(7):1076–1090. https://doi.org/10.1002/aur.1966
Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R, Leeman DS, George BM, Boutet SC, Hebestreit K, Pluvinage JV, Wyss-Coray T, Weissman IL, Vogel H, Davis MM, Brunet A (2019) Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571(7764):205–210. https://doi.org/10.1038/s41586-019-1362-5
Dupuis ML, Pagano MT, Pierdominici M, Ortona E (2021) The role of vitamin D in autoimmune diseases: could sex make the difference? Biol Sex Differ 12(1):12. https://doi.org/10.1186/s13293-021-00358-3
Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles ÁO, Medinas DB, Salazar C, Foley A, Gajardo I, Thielen P, Iwawaki T, Scheper W, Soto C, Palacios AG, Hoozeman JJM, Hetz C (2017) IRE1 signaling exacerbates Alzheimer’s disease pathogenesis. Acta Neuropathol 134(3):489–506. https://doi.org/10.1007/s00401-017-1694-x
Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N (2007) Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells. J Allergy Clin Immunol 119(4):982–990. https://doi.org/10.1016/j.jaci.2007.01.003
Efimova O, Szankasi P, Kelley TW (2011) Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of CD4+ effector T cells. PloS One 6(1):e16013. https://doi.org/10.1371/journal.pone.0016013
El-Ansary A, Al-Ayadhi L (2012) Lipid mediators in plasma of autism spectrum disorders. Lipids Health Dis 11:160. https://doi.org/10.1186/1476-511X-11-160
Feng J, Shan L, Du L, Wang B, Li H, Wang W, Wang T, Dong H, Yue X, Xu Z, Staal WG, Jia F (2017) Clinical improvement following vitamin D3 supplementation in Autism Spectrum Disorder. Nutr Neurosci 20(5):284–290. https://doi.org/10.1080/1028415X.2015.1123847
Fischer R, Maier O (2015) Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longevity 2015:610813. https://doi.org/10.1155/2015/610813
Freedman R, Hunter SK, Law AJ, Clark AM, Roberts A, Hoffman MC (2022) Choline, folic acid, Vitamin D, and fetal brain development in the psychosis spectrum. Schizophr Res 247:16–25. https://doi.org/10.1016/j.schres.2021.03.008
Frossi B, De Carli M, Piemonte M, Pucillo C (2008) Oxidative microenvironment exerts an opposite regulatory effect on cytokine production by Th1 and Th2 cells. Mol Immunol 45(1):58–64. https://doi.org/10.1016/j.molimm.2007.05.008
Frye RE, James SJ (2014) Metabolic pathology of autism in relation to redox metabolism. Biomark Med 8(3):321–330. https://doi.org/10.2217/bmm.13.158
Genovese A, Butler MG (2020) Clinical assessment, genetics, and treatment approaches in autism spectrum disorder (ASD). Int J Mol Sci 21(13):4726. https://doi.org/10.3390/ijms21134726
Ghezzi P (2011) Role of glutathione in immunity and inflammation in the lung. Int J Gen Med 4:105–113. https://doi.org/10.2147/IJGM.S15618
Ghosh A, Comerota MM, Wan D, Chen F, Propson NE, Hwang SH, Hammock BD, Zheng H (2020) An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease. Sci Transl Med 12(573):eabb1206. https://doi.org/10.1126/scitranslmed.abb1206
Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN (2010) Mitochondrial dysfunction in autism. JAMA 304(21):2389–2396. https://doi.org/10.1001/jama.2010.1706
Gu F, Chauhan V, Chauhan A (2013) Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: alterations in the activities and protein expression of glutathione-related enzymes. Free Rad Biol Med 65:488–496. https://doi.org/10.1016/j.freeradbiomed.2013.07.021
Haase H, Rink L (2007) Signal transduction in monocytes: the role of zinc ions. Biometals 20(3–4):579–585. https://doi.org/10.1007/s10534-006-9029-8
Heo Y, Zhang Y, Gao D, Miller VM, Lawrence DA (2011) Aberrant immune responses in a mouse with behavioral disorders. PloS one 6(7):e20912. https://doi.org/10.1371/journal.pone.0020912
Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A (2007) Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am J Med Genetics Part A 143A(6):589–593. https://doi.org/10.1002/ajmg.a.31619
Iskusnykh IY, Zakharova AA, Pathak D (2022) Glutathione in brain disorders and aging. Molecules 27(1):324. https://doi.org/10.3390/molecules27010324
Jackson SH, Devadas S, Kwon J, Pinto LA, Williams MS (2004) T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol 5(8):818–827. https://doi.org/10.1038/ni1096
Jacob ST, Ghoshal K, Sheridan JF (1999) Induction of metallothionein by stress and its molecular mechanisms. Gene Expr 7(4–6):301–310
Jeitner TM, Muma NA, Battaile KP, Cooper AJ (2009) Transglutaminase activation in neurodegenerative diseases. Future Neurol 4(4):449–467. https://doi.org/10.2217/fnl.09.17
Jia F, Wang B, Shan L, Xu Z, Staal WG, Du L (2015) Core symptoms of autism improved after vitamin D supplementation. Pediatrics 135(1):e196–e198. https://doi.org/10.1542/peds.2014-2121
Juárez-Rebollar D, Rios C, Nava-Ruíz C, Méndez-Armenta M (2017) Metallothionein in brain disorders. Oxid Med Cell Longev 2017:5828056. https://doi.org/10.1155/2017/5828056
Karin I, Borggraefe I, Catarino CB, Kuhm C, Hoertnagel K, Biskup S, Opladen T, Blau N, Heinen F, Klopstock T (2017) Folinic acid therapy in cerebral folate deficiency: marked improvement in an adult patient. J Neurol 264(3):578–582. https://doi.org/10.1007/s00415-016-8387-6
Kitic M, Wimmer I, Adzemovic M, Kögl N, Rudel A, Lassmann H, Bradl M (2014) Thymic stromal lymphopoietin is expressed in the intact central nervous system and upregulated in the myelin-degenerative central nervous system. Glia 62(7):1066–1074. https://doi.org/10.1002/glia.22662
Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, Suenaga F, Ohnuma Y, Ohba T, Katoh R, Sugiyam H, Hamada Y, Ogawa H, Okumura K, Nakao A (2007) A possible role for TSLP in inflammatory arthritis. Biochem Biophysical Res Com 357(1):99–104. https://doi.org/10.1016/j.bbrc.2007.03.081
Kumar V, Maity S (2021) ER stress-sensor proteins and ER-mitochondrial crosstalk-signaling beyond (ER) stress response. Biomol 11(2):173. https://doi.org/10.3390/biom11020173
Ledderose JMT, Benitez JA, Roberts AJ, Reed R, Bintig LME, Sachdev RNS, Furnari F, Eickholt BJ (2022) The impact of phosphorylated PTEN at threonine 366 on cortical connectivity and behaviour. Brain 145(10):3608–3621. https://doi.org/10.1093/brain/awac188
Lee PW, Selhorst A, Lampe SG, Liu Y, Yang Y, Lovett-Racke AE (2020) Neuron-specific vitamin D signaling attenuates microglia activation and CNS autoimmunity. Front Neurol 11:19. https://doi.org/10.3389/fneur.2020.00019
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207(1–2):111–116. https://doi.org/10.1016/j.jneuroim.2008.12.002
Liu X, Lin J, Zhang H, Khan NU, Zhang J, Tang X, Cao X, Shen L (2022) Oxidative stress in autism spectrum disorder-current progress of mechanisms and biomarkers. Front Psychiatry 13:813304. doi: https://doi.org/10.3389/fpsyt.2022.813304.
Lugrin J, Rosenblatt-Veli N, Parapanov R, Liaudet L (2014) The role of oxidative stress during inflammatory processes. Biol Chem 395(2):203–230. https://doi.org/10.1515/hsz-2013-0241
Lushchak VI (2012) Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids, 2012:736837. https://doi.org/10.1155/2012/736837
Maares M, Haase H (2016) Zinc and immunity: an essential interrelation. Arch Biochem Biophys 611:58–65. https://doi.org/10.1016/j.abb.2016.03.022
Maenner MJ, Shaw KA, Bakian AV, Bilder DA, Durkin MS, Esler A, Furnier SM, Hallas L, Hall-Lande J, Hudson A, Hughes MM, Patrick M, Pierce K, Poynter JN, Salinas A, Shenouda J, Vehorn A, Warren Z, Constantino JN, DiRienzo M, Fitzgerald RT, Grzybowski A, Spivey MH, Pettygrove S, Zahorodny W, Ali A, Andrews JG, Baroud T, Gutierrez J, Hewitt A, Lee LC, Lopez M, Mancilla KC, McArthur D, Schwenk YD, Washington A, Williams S, Cogswell ME (2021) Prevalence and characteristics of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2018. MMWR Surveill Summ 70(11):1–16. https://doi.org/10.15585/mmwr.ss7011a1
Manso Y, Adlard PA, Carrasco J, Vašák M, Hidalgo J (2011) Metallothionein and brain inflammation. J Biol Inorg Chem 16:1103. https://doi.org/10.1007/s00775-011-0802-y
McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN (2008) Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 7(2):152–163. https://doi.org/10.1111/j.1601-183X.2007.00330.x
Meguid NA, Bjørklund G, Gebril OH, Doşa MD, Anwar M, Elsaeid A, Gaber A, Chirumbolo S (2019) The role of zinc supplementation on the metallothionein system in children with autism spectrum disorder. Acta Neurol Belg 119(4):577–583. https://doi.org/10.1007/s13760-019-01181-9
Moro-García MA, Mayo JC, Sainz RM, Alonso-Arias R (2018) Influence of inflammation in the process of T lymphocyte differentiation: proliferative, metabolic, and oxidative changes. Front Iimmunol 9:339. https://doi.org/10.3389/fimmu.2018.00339
Moscavitch SD, Szyper-Kravitz M, Shoenfeld Y (2009) Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: the olfactory and immune system interrelationship. Clin Immunol 130(3):235–243. https://doi.org/10.1016/j.clim.2008.10.010
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136(7):2348–2357
Nadeem A, Ahmad SF, Al-Harbi NO, Attia SM, Alshammari MA, Alzahrani KS, Bakheet SA (2019) 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. Prog Neuro-Psychopharm Biol Psychiatry 89:245–253. https://doi.org/10.1016/j.pnpbp.2018.09.012
Nadeem A, Ahmad SF, Attia SM, Al-Ayadhi LY, Al-Harbi NO, Bakheet SA (2020) Dysregulation in IL-6 receptors is associated with upregulated IL-17A related signaling in CD4+ T cells of children with autism. Prog Neuro-psychopharmacology Biological Psychiatry 97:109783. https://doi.org/10.1016/j.pnpbp.2019.109783
Napoli E, Wong S, Hertz-Picciotto I, Giulivi C (2014) Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics 133(5):e1405–e1410. https://doi.org/10.1542/peds.2013-1545
Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfel, R, Giulivi C (2012) Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PloS one, 7(8), e42504. https://doi.org/10.1371/journal.pone.0042504
Noack M, Miossec P (2014) Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13(6):668–677. https://doi.org/10.1016/j.autrev.2013.12.004
Pangrazzi L, Balasco L, Bozzi Y (2020) Oxidative stress and immune system dysfunction in autism spectrum disorders. Int J Mol Sci 21(9):3293. https://doi.org/10.3390/ijms21093293
Peretti S, Mariano M, Mazzocchetti C, Mazza M, Pino MC, Verrotti Di Pianella A, Valenti M (2019) Diet: the keystone of autism spectrum disorder? Nutr Neurosci 22(12):825–839
Peterson JD, Herzenberg LA, Vasquez K, Waltenbaugh C (1998) Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc National Acad Sci USA 95(6):3071–3076. https://doi.org/10.1073/pnas.95.6.3071
Plantone D, Prmiano G, Manco C, Locci S, Servidei S, De Stefano N (2022) Vitamin D in neurological diseases. Int j Mol Sci 24(1):87. https://doi.org/10.3390/ijms24010087
Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM (2013) ROS and brain diseases: the good, the bad, and the ugly. Oxidat Med Cell Longevity 2013:963520. https://doi.org/10.1155/2013/963520
Ramaekers VT, Sequeira JM, Thöny B, Quadros EV (2020) Oxidative stress, folate receptor autoimmunity, and CSF findings in severe infantile autism. Autism Res Treat 2020:9095284. https://doi.org/10.1155/2020/9095284
Rose S, Niyazov DM, Rossignol DA, Goldenthal M, Kahler SG, Frye RE (2018) Clinical and molecular characteristics of mitochondrial dysfunction in autism spectrum disorder. Mol Diagn Ther 22(5):571–593. https://doi.org/10.1007/s40291-018-0352-x
Rose S, Frye RE, Slattery J, Wynne R, Tippett M, Pavliv O, Melnyk S, James SJ (2014) Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. PloS One 9(1):e85436. https://doi.org/10.1371/journal.pone.0085436
Rout UK, Clausen P (2009) Common increase of GATA-3 level in PC-12 cells by three teratogens causing autism spectrum disorders. Neurosci Res 64(2):162–169. https://doi.org/10.1016/j.neures.2009.02.009
Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, Cannell JJ, Bjørklund G, Abdel-Reheim MK, Othman HA, El-Houfey AA, Abd El-Aziz NH, Abd El-Baseer KA, Ahmed AE, Ali AM (2016) Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. Nutr Neurosci 19(8):346–351. https://doi.org/10.1179/1476830515Y.0000000019
Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13(6):461–467. https://doi.org/10.1038/nri3464
Salzano S, Checconi P, Hanschmann EM, Lillig CH, Bowler LD, Chan P, Vaudry D, Mengozzi M, Coppo ., Sacre S, Atkuri KR, Sahaf B, Herzenberg LA, Herzenberg LA, Mullen L, Ghezzi P (2014) Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proc National Acad Sci USA 111(33):12157-12162https://doi.org/10.1073/pnas.1401712111
Schulze-Koops H, Kalden JR (2001) The balance of Th1/Th2 cytokines in rheumatoid arthritis. Best Practice & Research Clin Rheum 15(5):677–691. https://doi.org/10.1053/berh.2001.0187
Shemer A, Erny D, Jung S, Prinz M (2015) Microglia plasticity during health and disease: an immunological perspective. Trend Immunol 36(10):614–624. https://doi.org/10.1016/j.it.2015.08.003
Silverman JL, Pride MC, Hayes JE, Puhger KR, Butler-Struben HM, Baker S, Crawley JN (2015) GABAB receptor agonist r-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacol 40(9):2228–2239. https://doi.org/10.1038/npp.2015.66
Smolders J, Heutinck KM, Fransen NL, Remmerswaal EBM, Hombrin P, Ten Berge IJM, van Lier RAW, Huitinga I, Hamann J (2018) Tissue-resident memory T cells populate the human brain. Nat Comm 9(1):4593. https://doi.org/10.1038/s41467-018-07053-9
Steinman L (2004) Elaborate interactions between the immune and nervous systems. Nat Immunol 5(6):575–581. https://doi.org/10.1038/ni1078
Szodoray P, Nakken B, Gaal J, Jonsson R, Szegedi A, Zold E, Szegedi G, Brun JG, Gesztelyi R, Zeher M, Bodolay E (2008) The complex role of vitamin D in autoimmune diseases. Scand J Immunol 68(3):261–269. https://doi.org/10.1111/j.1365-3083.2008.02127.x
Tan M, Yang T, Zhu J, Li Q, Lai X, Li Y, Tang T, Chen J, Li T (2020) Maternal folic acid and micronutrient supplementation is associated with vitamin levels and symptoms in children with autism spectrum disorders. Reprod Toxicol 91:109–115. https://doi.org/10.1016/j.reprotox.2019.11.009
Tse HM, Thayer TC, Steele C, Cuda CM, Morel L, Piganelli JD, Mathews CE (2010) NADPH oxidase deficiency regulates Th lineage commitment and modulates autoimmunity. J Immunol 185(9):5247–5258. https://doi.org/10.4049/jimmunol.1001472
Uddin MN, Yao Y, Mondal T, Matala R, Manley K, Lin Q, Lawrence DA (2020a) Immunity and autoantibodies of a mouse strain with autistic-like behavior. Brain Behav Immun Health, 4:100069. https://doi.org/10.1016/j.bbih.2020.100069
Uddin MN, Yao Y, Manley K, Lawrence DA (2020b) Development, phenotypes of immune cells in BTBR T+Itpr3tf/J mice. Cell Immunol. 358:104223. https://doi.org/10.1016/j.cellimm.2020.104223
Uddin MN, Manley K, Lawrence DA (2022) Altered meningeal immunity contributing to the autism-like behavior of BTBR T+ Itpr3tf/J mice. Brain Behav Immun Health 26:100563. https://doi.org/10.1016/j.bbih.2022.100563
van Doorninck JH, van Der Wees J, Karis A, Goedknegt E, Engel JD, Coesmans M, Rutteman M, Grosveld F, De Zeeuw CI (1999) GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei. J Neurosci 19(12):RC12. https://doi.org/10.1523/JNEUROSCI.19-12-j0002.1999
Voet S, Prinz M, van Loo G (2019) Microglia in central nervous system inflammation and multiple sclerosis pathology. Trend Mol Med 25(2):112–123. https://doi.org/10.1016/j.molmed.2018.11.005
Wang T, Shan L, Du L, Feng J, Xu Z, Staal WG, Jia F (2016) Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry 25(4):341–350. https://doi.org/10.1007/s00787-015-0786-1
Wang Y, Guo X, Hong X, Wang G, Pearson C, Zuckerman B, Clark AG, O’Brien KO, Wang X, Gu Z (2022) Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism. Nat Commun 13(1):3790. https://doi.org/10.1038/s41467-022-30805-7
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J (2007) Autoantibodies in autism spectrum disorders (ASD). Ann New York Acad Sci 1107:79–91.https://doi.org/10.1196/annals.1381.009
Wischhusen J, Melero I, Fridman WH (2020) Growth/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint. Front Immunol 11:951. https://doi.org/10.3389/fimmu.2020.00951
Wöhr M, Roullet FI, Crawley JN (2011) Reduced scent marking and ultrasonic vocalizations in the BTBR T+tf/J mouse model of autism. Genes Brain Behav 10(1):35–43. https://doi.org/10.1111/j.1601-183X.2010.00582.x
Yao Y, Uddin MN, Manley K, Lawrence DA (2022) Improvements of autism-like behaviors but limited effects on immune cell metabolism after mitochondrial replacement in BTBR T+Itpr3tf/J mice. J Neuroimmunol 368:577893. https://doi.org/10.1016/j.jneuroim.2022.577893
Yin X, Knecht DA, Lynes MA (2005) Metallothionein mediates leukocyte chemotaxis. BMC Immunol 6:21. https://doi.org/10.1186/1471-2172-6-21
Ying S, O’Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 174(12):8183–8190. https://doi.org/10.4049/jimmunol.174.12.8183
Zhang Y, Gao D, Kluetzman K, Mendoza A, Bolivar VJ, Reilly A, Jolly JK, Lawrence DA (2013) The maternal autoimmune environment affects the social behavior of offspring. J Neuroimmunol 258(1–2):51–60. https://doi.org/10.1016/j.jneuroim.2013.02.19
Zhu J, Yamane H, Cote-Sierra J, Guo L, Paul WE (2006) GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res 16(1):3–10. https://doi.org/10.1038/sj.cr.7310002
Acknowledgements
We thank Dr. Michael Lynes (University of Connecticut Storrs) for his monoclonal antibody (UC1MT) to metallothionein.
Funding
The study was funded by a grant to DAL from NIEHS R01ES025584.
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Uddin, M.N., Mondal, T., Yao, Y. et al. Oxidative stress and neuroimmune proteins in a mouse model of autism. Cell Stress and Chaperones 28, 201–217 (2023). https://doi.org/10.1007/s12192-023-01331-2
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DOI: https://doi.org/10.1007/s12192-023-01331-2