Immune function changes of the IDPN‐induced Tourette syndrome rat model

Abstract

There may be immunologic alternations during Tourette syndrome (TS) development. This study aimed to determine the immune function changes in different aspects (spleen or thymus index, plasma cytokines, and T cell) in an 3,3′‐iminodipropionitrile (IDPN)‐induced rat model of TS. Male Sprague‐Dawley rats were assigned to control and TS groups. The control group received intraperitoneal infections of normal saline (5 ml kg−1 day−1), and the TS rats were injected with IDPN (150 mg kg−1 day−1). The spleen and thymus indices were calculated. The expression of anti‐inflammatory cytokines and inflammatory cytokines TNF‐α, in peripheral blood were measured by ELISA and Western blotting. The proportion of CD3+, CD4+, CD8+, Treg, Th1, and Th2 cells were determined by fluorescence‐activated cell sorting analysis. After 1 week of IDPN treatment, TS rats had decreased spleen and thymus weights versus control. The plasma levels of IL‐4, IL‐10, IL‐12, IFN‐γ, and TNF‐α were significantly increased, while no significant difference in TGF‐β was found. Flow cytometry analysis demonstrated that TS rats had significantly reduced CD3+ and CD4+ cells in spleen, without any change in the proportion of CD8+ cells. Furthermore, the ratio of Treg cells (CD4+/CD25+/FoxP3+) was decreased in TS rats; simultaneously, Th1 cells (CD4+/IFN‐γ+) and Th2 cells (CD4+/IL4+) were dramatically increased. Together, IDPN can trigger immune dysfunction through impairment of matured Th cells, in particular for the Treg subset.

Neuroinflammation in a Rat Model of Tourette Syndrome

“…Our study showed that the rat model of TS with DA dysregulation constructed using IDPN had significantly higher cytokines like IL-6 and TNF-α in the brain than in the normal group. The present data confirmed and extended prior findings that TS rats were associated with increased cytokines expression ( Long et al, 2019b ; Liu et al, 2020 ). Long et al (2019a) also found highly elevated cytokines in a TS model constructed using the 5-hydroxytryptamine agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI).…”

“…These results support the existence of a link between immunity dysfunction and behavioral stereotypes. The TS animal models [ours and previous studies (Long et al, 2019a,b;Liu et al, 2020)] constructed by neurotransmitter dysfunction showed increased cytokines, which may also indicate an interaction between neurotransmitters and neuroinflammation in TS disorders. Animal models constructed by IDPN mainly lead to a decrease in DA neurotransmission (Nobuo Wakata, 2000), and some studies have found that decreased CNS DA leads to increased neurological inflammation (Pajares et al, 2020).…”

“…It disrupts the DA in the extrapyramidal system, resulting in a persistent decrease in DA concentration (Nobuo Wakata, 2000), leading to DA receptor hypersensitivity during growth and development, which could result in stereotypical behaviors in animals (Yanhui, 2020). The IDPN model is a standard animal model for TS, which can reproduce the behavioral characteristics of TS comprehensively; it had been used in many experiments of TS (Zhang and Li, 2015;Zhao et al, 2015;Lin et al, 2019;Liu et al, 2020). Although tic disorders are a prevalent developmental disease in children, the etiology and pathogenesis of tic disorders are still unclear.…”

“… Parker-Athill et al (2015) also found that the serum IL-4, IL-8, and IL-17 of children with tic symptoms were considerably higher than those of normal children. The study by Liu et al (2020) , like ours, used IDPN to construct an animal model of TS, which found that plasma IL-4, IL-10, IL-12, IFN-γ, and TNF-α levels were significantly increased in TS rats, while TGF-β levels were not entirely different; Liu’s study involved mainly the immune response in the periphery of TS rats, while our study focused on the inflammation of the central nervous system (CNS) in TS rats.…”

Effects of Chemogenetic Inhibition of D1 or D2 Receptor-Containing Neurons of the Substantia Nigra and Striatum in Mice With Tourette Syndrome

“…3,3′-Iminodipropionitrile (IDPN) is a synthetic organic nitrile, and it is the most commonly used inducer of TS in animal models as its effects can last a long time ( Wang et al, 2013 , 2021 ; Zhang et al, 2014 ; Zhang and Li, 2015a , b ; Xie et al, 2016 ; Chen et al, 2019 ; Zhao et al, 2020 ; Liu et al, 2021 ). Our previous research results also showed that IDPN induced abnormal stereotyped behavior in mice ( Lin et al, 2019 ), which caused a behavioral syndrome in rodents similar to the symptoms of patients with TS, such as featuring lateral and vertical head-shakes, random circling, hyperactivity, and elevated acoustic startle response ( Khan and Ibrahim, 2015 ; Zhang and Li, 2015c ; Wang et al, 2021 ).…”