A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii

He, Yan; Xu, Daxiang; Yan, Ziyi; Wu, Yongshuai; Zhang, Yongsheng; Tian, Xiaokang; Zhu, Jie; Liu, Zhuanzhuan; Cheng, Wanpeng; Zheng, Kuiyang; Yang, Xiaoying; Yu, Yinghua; Pan, Wei

doi:10.3389/fimmu.2022.1043572

Cited by 12 publications

(14 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in contrast, activation of STAT1/3 by ACOD1‐induced ROS also caused cytokine accumulation 56 . Inhibition of ACOD1 causes microglia forming a protective subtype and promotes neuronal regeneration after parasite or virus infection 57,24 . Although the pathogenesis of post‐SCI neuroinflammation is triggered by mechanical injury‐induced fragmentised cells and tissue, our findings also suggested that the absence of ACOD1 aggravated OS and the inflammatory response in either SCI mice or debris‐treated microglia.…”

Section: Discussionmentioning

confidence: 70%

“…Through protein modification of Keap1 via alkylation of its cysteine residues, Ita promotes Nrf2 expression, which enhances transcription of downstream genes that exert anti‐inflammatory/oxidative functions 19,21 . Because of this property, Ita and its derivative 4‐octyl itaconate (4‐OI) have been suggested as a potential target for the therapy of various diseases including liver injury, neuronal infection and pulmonary fibrosis 22–24 . Our recent study confirmed that the expression of ACOD1 was markedly increased in inflammatory microglia after LPS stimulation 25 .…”

Section: Introductionmentioning

confidence: 57%

See 1 more Smart Citation

ACOD1, rather than itaconate, facilitates p62‐mediated activation of Nrf2 in microglia post spinal cord contusion

Qian,

Xia,

Zhao

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundSpinal cord injury (SCI)‐induced neuroinflammation and oxidative stress (OS) are crucial events causing neurological dysfunction. Aconitate decarboxylase 1 (ACOD1) and its metabolite itaconate (Ita) inhibit inflammation and OS by promoting alkylation of Keap1 to induce Nrf2 expression; however, it is unclear whether there is another pathway regulating their effects in inflammation‐activated microglia after SCI.MethodsAdult male C57BL/6 ACOD1−/− mice and their wild‐type (WT) littermates were subjected to a moderate thoracic spinal cord contusion. The degree of neuroinflammation and OS in the injured spinal cord were assessed using qPCR, western blot, flow cytometry, immunofluorescence, and trans‐well assay. We then employed immunoprecipitation‐western blot, chromatin immunoprecipitation (ChIP)‐PCR, dual‐luciferase assay, and immunofluorescence‐confocal imaging to examine the molecular mechanisms of ACOD1. Finally, the locomotor function was evaluated with the Basso Mouse Scale and footprint assay.ResultsBoth in vitro and in vivo, microglia with transcriptional blockage of ACOD1 exhibited more severe levels of neuroinflammation and OS, in which the expression of p62/Keap1/Nrf2 was down‐regulated. Furthermore, silencing ACOD1 exacerbated neurological dysfunction in SCI mice. Administration of exogenous Ita or 4‐octyl itaconate reduced p62 phosphorylation. Besides, ACOD1 was capable of interacting with phosphorylated p62 to enhance Nrf2 activation, which in turn further promoted transcription of ACOD1.ConclusionsHere, we identified an unreported ACOD1‐p62‐Nrf2‐ACOD1 feedback loop exerting anti‐inflammatory and anti‐OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita. The present study extends the functions of ACOD1 and uncovers marked property differences between endogenous and exogenous Ita.Key points ACOD1 attenuated neuroinflammation and oxidative stress after spinal cord injury. ACOD1, not itaconate, interacted with p‐p62 to facilitate Nrf2 expression and nuclear translocation. Nrf2 was capable of promoting ACOD1 transcription in microglia.

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 57%

ACOD1, rather than itaconate, facilitates p62‐mediated activation of Nrf2 in microglia post spinal cord contusion

Qian,

Xia,

Zhao

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…Our previous study also showed that the derivative of itaconate could ameliorate the hippocampus-associated cognitive deficits in T . gondii infected mice [ 41 ]. Overall, these results suggest that itaconate may be a promising therapeutic molecular to treat neurodegenerative diseases including T .…”

Section: Discussionmentioning

confidence: 99%

“…gondii cysts by the gavage (10 cysts for each mouse) as Tg group. The detailed process of infection was carried out as previously reported [ 41 ].…”

Section: Methodsmentioning

confidence: 99%

Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice

et al. 2023

PLoS Negl Trop Dis

Self Cite

View full text Add to dashboard Cite

Background The neurotrophic parasite Toxoplasma gondii (T. gondii) has been implicated as a risk factor for neurodegenerative diseases. However, there is only limited information concerning its underlying mechanism and therapeutic strategy. Here, we investigated the effects of T. gondii chronic infection on the goal-directed cognitive behavior in mice. Moreover, we evaluated the preventive and therapeutic effect of dimethyl itaconate on the behavior deficits induced by the parasite. Methods The infection model was established by orally infecting the cysts of T. gondii. Dimethyl itaconate was intraperitoneally administered before or after the infection. Y-maze and temporal order memory (TOM) tests were used to evaluate the prefrontal cortex-dependent behavior performance. Golgi staining, transmission electron microscopy, indirect immunofluorescence, western blot, and RNA sequencing were utilized to determine the pathological changes in the prefrontal cortex of mice. Results We showed that T. gondii infection impaired the prefrontal cortex-dependent goal-directed behavior. The infection significantly downregulated the expression of the genes associated with synaptic transmission, plasticity, and cognitive behavior in the prefrontal cortex of mice. On the contrary, the infection robustly upregulated the expression of activation makers of microglia and astrocytes. In addition, the metabolic phenotype of the prefrontal cortex post infection was characterized by the enhancement of glycolysis and fatty acid oxidation, the blockage of the Krebs cycle, and the disorder of aconitate decarboxylase 1 (ACOD1)-itaconate axis. Notably, the administration of dimethyl itaconate significantly prevented and treated the cognitive impairment induced by T. gondii, which was evidenced by the improvement of behavioral deficits, synaptic ultrastructure lesion and neuroinflammation. Conclusion The present study demonstrates that T. gondii infection induces the deficits of the goal-directed behavior, which is associated with neuroinflammation, the impairment of synaptic ultrastructure, and the metabolic shifts in the prefrontal cortex of mice. Moreover, we report that dimethyl itaconate has the potential to prevent and treat the behavior deficits.

show abstract

“…Interestingly, exogenous ITA reduces the bacterial burden, and the physiologic concentration of ITA is sufficient to control C. burnetii replication ( 43 ). Furthermore, in chronic infection with Toxoplasma gondii , which impairs cognitive functions, treatment of infected mice with DMI improves behavioral performance and ameliorates microglial inflammation ( 44 ).…”

Section: Roles Of Ita In Infectionmentioning

confidence: 99%

Itaconate family-based host-directed therapeutics for infections

et al. 2023

View full text Add to dashboard Cite

Itaconate is a crucial anti-infective and anti-inflammatory immunometabolite that accumulates upon disruption of the Krebs cycle in effector macrophages undergoing inflammatory stress. Esterified derivatives of itaconate (4-octyl itaconate and dimethyl itaconate) and its isomers (mesaconate and citraconate) are promising candidate drugs for inflammation and infection. Several itaconate family members participate in host defense, immune and metabolic modulation, and amelioration of infection, although opposite effects have also been reported. However, the precise mechanisms by which itaconate and its family members exert its effects are not fully understood. In addition, contradictory results in different experimental settings and a lack of clinical data make it difficult to draw definitive conclusions about the therapeutic potential of itaconate. Here we review how the immune response gene 1-itaconate pathway is activated during infection and its role in host defense and pathogenesis in a context-dependent manner. Certain pathogens can use itaconate to establish infections. Finally, we briefly discuss the major mechanisms by which itaconate family members exert antimicrobial effects. To thoroughly comprehend how itaconate exerts its anti-inflammatory and antimicrobial effects, additional research on the actual mechanism of action is necessary. This review examines the current state of itaconate research in infection and identifies the key challenges and opportunities for future research in this field.

show abstract

A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii

Cited by 12 publications

References 89 publications

ACOD1, rather than itaconate, facilitates p62‐mediated activation of Nrf2 in microglia post spinal cord contusion

ACOD1, rather than itaconate, facilitates p62‐mediated activation of Nrf2 in microglia post spinal cord contusion

Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice

Itaconate family-based host-directed therapeutics for infections

Contact Info

Product

Resources

About