Objective To investigate the activation and mechanism of microglia (MG) in Tourette syndrome (TS) rats induced by 3,3'-aminodipropionitrile (IDPN). Methods Thirty six male Sprague Dawley rats were randomly divided into a TS group and a Sham group (Sham group),with 18 rats in each group.The TS group received intraperitoneal injection of IDPN for 7 days,with the dose of 300mg/(kg·d),while the Sham group received intraperitoneal injection of physiological saline for 7 days,with the dose of 5mL/(kg·d).Double immunofluorescence staining was used to detected the expression of inducible nitric oxide synthase (iNOS),a marker protein of M1 type microglia,and its co-localization with Iba-1(a specific marker for microglial activation) in rat striatum,as well as the expression of arginase 1 (Arg-1) and its co-location with Iba-1 in M2 microglia.The expression levels of iNOS,Arg-1 in rat striatal tissues were quantified by enzyme-linked immunosorbent measurement (ELISA),real-time PCR (qRT-PCR),meanwhile the expression levels of inflammatory cytokines tumor necrosis factor α (TNF-α),interleukin-6(IL-6),and interleukin-10(IL-10) were detected. Results Immunofluorescence double staining showed that the positive expressions of Iba-1 and iNOS in striatum of TS group were enhanced and co-located compared with Sham group,while the positive expression of Iba-1 and Arg-1 in striatum of TS group decreased and showed co-localization.The ELISA results showed that compared with the Sham group,the TS group had a significant increase in the content of M1 type MG marker protein iNOS (t=5.796,P<0.001),a significant decrease in the content of M2 type MG marker protein Arg-1 (t=4.348,P<0.01),and a significant increase in inflammatory factors,including TNF-α,IL-6 and IL-10 (t=5.654,5.748,8.231, P<0.001).The qRT-PCR results showed that compared with the Sham group,the mRNA expression level of iNOS,a M1 type MG marker protein,was significantly increased in the TS group (t=9.914,P<0.001),while the mRNA expression level of Arg-1,a M2 type MG marker protein,was significantly reduced (t=4.390,P<0.01),and the mRNA expression levels of inflammatory factors in the TS group,including TNF-α,IL-6 and IL-10 were significantly increased (t=12.056,14.147,13.350,P<0.001). Conclusion TS rats induced by IDPN exhibit MG activation,with M1 type MG upregulated and M2 type MG downregulated,thereby mediating neuroinflammation.
Key words
Tourette syndrome /
microglia /
neuroimmunity /
inflammatory factor
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
[1] Eapen V,Usherwood T.Tourette syndrome in children[J].Aust J Gen Pract,2021(50):120-125.
[2] Set KK,Warner JN.Tourette syndrome in children: An update[J].Curr Probl Pediatr Adolesc Health Care,2021(51): 101032.
[3] Martino D,Johnson I,Leckman JF.What does immunology have to do with normal brain development and the pathophysiology underlying Tourette syndrome and related neuropsychiatric disorders?[J].Front Neurol,2020(11): 567407.
[4] Hsu Chia-Jui,Wong Lee-Chin,Lee Wang-Tso.Immunological dysfunction in Tourette syndrome and related disorders[J].Int J Mol Sci,2021,22(2):doi:853.
[5] Eyo UB,Wu LJ.Microglia: Lifelong patrolling immune cells of the brain[J].Prog Neurobiol,2019(179): 101614.
[6] Tay TL,Savage JC,Hui CW,et al.Microglia across the lifespan: From origin to function in brain development,plasticity and cognition[J].J Physiol,2017(595): 1929-1945.
[7] Ransohoff RM.A polarizing question:Do M1 and M2 microglia exist?[J].Nat Neurosci,2016(19):987-991.
[8] Orihuela R,McPherson CA,Harry GJ.Microglial M1/M2 polarization and metabolic states[J].Br J Pharmacol,2016(173):649-665.
[9] Kumar JM,Won-Ha L,Kyoungho S.Functional polarization of neuroglia: Implications in neuroinflammation and neurological disorders[J].Biochem Pharmacol,2016(103):1-16.
[10] Martino D,Zis P,Buttiglione M.The role of immune mechanisms in Tourette syndrome[J].Brain Res,2015(1617):126-143.
[11] Lennington JB,Coppola G,Kataoka-Sasaki Y,et al.Transcriptome analysis of the human striatum in Tourette syndrome[J].Biol.Psychiatry,2016(79):372-382.
[12] Kumar A,Williams MT.Chugani HT.Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and Tourette syndrome:A positron emission tomographic (PET) study using 11C-[R]-PK11195[J].J Child Neurol,2015(30):749-756.
[13] Diamond BI,Reyes MG,Borison R.A new animal model for Tourette syndrome[J].Adv Neurol,1982(35):221-225.
[14] Chou CY,Agin-Liebes J,Sheng-Han K,et al,Emerging therapies and recent advances for Tourette syndrome[J].Heliyon,2023(9): e12874.
[15] Gong H,Du X,Su A,et al.Pharmacological treatment of Tourette's syndrome: From the past to the future[J].Neurol Sci,2024(45):941-962.
[16] Khan K,Hollis C,Murphy T,et al.Digital and remote behavioral therapies for treating tic disorders: Recent advances and next steps[J].Front Psychiatry,2022(13): 928487.
[17] Lin WD,Tsai FJ,Chou IC.Current understanding of the genetics of Tourette syndrome[J].Biomed J,2022,45(2):271-279.
[18] Maia TV,Conceição VA.Dopaminergic disturbances in Tourette syndrome: An integrative account[J].Biol Psychiatry,2018(84): 332-344.
[19] Dwyer JB,Ross DA.Modern microglia:Novel targets in psychiatric neuroscience[J].Biol Psychiatry,2016(80): e47-49.
[20] Wohleb ES,Delpech JC.Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences[J].Prog Neuro-Psychoph,2017,79(Pt A): 40-48.
[21] Umpierre AD,Wu LJ.How microglia sense and regulate neuronal activity[J].Glia,2021(69): 1637-1653.
[22] Chhor V,Le Charpentier T,Lebon S,et al.Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro[J].Brain Behav Immun,2013(32):70-85.
[23] Büttner P,Werner S,Baskal S,et al.Arginine metabolism and nitric oxide turnover in the ZSF1 animal model for heart failure with preserved ejection fraction[J].Sci Rep,2021(11): 20684.
[24] 刘艳艳,陈燕惠.亚氨基二丙腈构建的抽动障碍大鼠脑组织IL-6及TNF-α变化及意义[J].中国神经免疫学和神经病学杂志,2014,21(5): 340-343.
Liu YY,Chen YH.Changes and significance of IL-6 and TNF-α in brain tissue of rats with tic disorder induced by iminodipropionitrile[J].Chinese Journal of Neuroimmunology and Neurology,2014,21 (5): 340-343.(in Chinese)
[25] Salvador AF,de Lima KA,Kipnis J.Neuromodulation by the immune system: A focus on cytokines[J].Nat Rev Immunol,2021(21):526-541.
[26] Hong JJ,Loiselle CR,Yoon DY,et al.Microarray analysis in Tourette syndrome postmortem putamen[J].J Neurol Sci,2004(225):57-64.
[27] Morer A,Chae W,Henegariu O,et al.Elevated expression of MCP-1,IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases[J].Brain Behav Immun,2010(24): 1069-1073.
[28] Liu X,Wang X,Cao A,et al.Immune function changes of the IDPN-induced Tourette syndrome rat model[J].Int J Dev Neurosci,2021(81):159-166.
[29] Leckman JF,Katsovich L,Kawikova I,et al.Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette's syndrome[J].Biol Psychiatry,2005(57): 667-673.
[30] Gabbay V,Coffey BJ,Guttman LE,et al.A cytokine study in children and adolescents with Tourette's disorder[J].Prog Neuropsychopharmacol Biol Psychiatry,2009(33):967-971.
[31] Cheng YH,Zheng Y,He F,et al.Detection of autoantibodies and increased concentrations of interleukins in plasma from patients with Tourette's syndrome[J].J Mol Neurosci,2012(48):219-224.
[32] Gosselin D,Rivest S.MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation[J].Molecular psychiatry,2008(13):480-497.
[33] Serrats J,Schiltz JC,Garcia-Bueno B,et al.Dual roles for perivascular macrophages in immune-to-brain signaling[J].Neuron,2010(65):94-106.
[34] Dantzer R.Cytokine-induced sickness behavior: Mechanisms and implications[J].Annals of the New York Academy of Sciences,2001(933):222-234.
[35] Wohleb ES,Powell ND,Godbout JP,et al.Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior[J].The Journal of Neuroscience,2013(33):13820-13833.
PDF(2975 KB)
