BackgroundNeurodegenerative diseases including AD is currently one of intractable problems globally due to the insufficiency of intervention strategies. Long-term infection of Toxoplasma gondii (T. gondii) can induce cognitive impairment in hosts, which is closely implicated in the pathogenesis of neurodegenerative diseases. Aconitate decarboxylase 1 (Acod1) and its produced metabolite itaconate (termed Acod1/itaconate axis), have recently attracted extensive interests due to its anti-inflammatory role in macrophages. However, whether the axis can influence cognitive function remains unknown. MethodsA chronic T. gondii-infected mice (C57BL/6J) model was established via administration of cysts by gavage. Novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests were used to evaluate the behavior performance. Transmission electron microscopy, immunofluorescence, RT-PCR, western-blotting and RNA sequencing were utilized to determine the pathological changes, neuroinflammation and transcription profile in hippocampus tissues post infection, respectively. Moreover, the protective effect of Acod1/itaconate axis in T. gondii-induced cognitive deficits was evaluated.ResultsWe found that the latent infection of the parasite impaired the cognitive function, which was assessed behaviorally by novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests. RNA sequencing of hippocampus showed that the infection downregulated the expression of genes related to synaptic plasticity, transmission and cognitive behavior. To our attention, the infection robustly upregulated the expression of genes associated with pro-inflammatory responses, which was characterized by microglia activation and disorder of Acod1/itaconate axis. Interestingly, administration of dimethyl itaconate (DI, an itaconate derivative with cell membrane permeability) could significantly ameliorate the cognitive deficits induced by T. gondii, which was proved by improvement of behavior performance and synaptic ultrastructure impairment, and lower accumulation of pro-inflammatory microglia. Notably, DI administration had a potential therapeutic effect on the cognitive deficits and synaptic impairment induced by the parasitic infection.ConclusionsOverall, these findings provide a novel insight for the pathogenesis of T. gondii-related cognitive deficits in hosts, and also provide a novel clue for the potential therapeutic strategies.

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease that causes cartilage and bone damage or even disability, seriously endangering human health. Chronic synovial in ammation has been shown to play a vital role in the disease sustainability. Therefore, down-regulation of synovial in ammation is considered to be an effective discipline for RA therapy. Polyene phosphatidylcholine (PPC) is a hepatoprotective agent, which was observed to inhibit in ammation in macrophages and prevent collagen-induced arthritis (CIA) of rats in our previous study. However, the underlying mechanism remains unclear. The present study further reported that PPC can inhibit the synovial in ammation. In lipopolysaccharide (LPS)-stimulated primary synovial broblasts (SFs) of mice, PPC signi cantly decreased pro-in ammatory cytokines production while increasing anti-in ammatory cytokines level. In this process, PPC down-regulated the expression of TLR-2 and their downstream signaling molecules such as MyD88, p-ERK1/2, p-JNK1/2, p-P38 in the MAPK pathway and p-IκBα and NF-κB-p65 in NF-kB pathway. Moreover, the inhibitory effect of PPC on the above molecules and cytokines was weakened after the use of TLR-2 agonist Pam3CSK4. However, PPC lost its anti-in ammatory effect and showed an activation of MAPK and NF-kB pathways in the TLR-2 -/primary SFs after exposure to LPS. Furthermore, these results were con rmed in the SFs from the CIA mouse ex vivo. Collectively, this study demonstrated that PPC can alleviate synovial in ammation through TLR-2 mediated MAPK and NF-κB pathways, which can be proposed to be a potential drug candidate for RA therapy.

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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.

BackgroundWe previously reported that the larval Echinococcus granulosus (E. granulosus) infection can expand the population of regulatory B cells in mice, thereby inhibiting the anti-infective immunity. However, the underlying mechanism is still largely unknown. This study further investigated the holistic transcriptomic profiles of total splenic B cells following the chronic infection of the parasite.MethodsThe infection model of larval E. granulosus was established by intraperitoneal inoculation with 2000 protoscolexes. Magnetic-Activated Cell Separation (MACS) was used to isolate the total splenic B cells. RNA sequencing was performed to screen the differentially expressed genes (DEGs) after infection. The expression of selected DEGs was verified using qRT-PCR. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Co-expression network analysis were applied to predict these DEGs' underlying biological processes, pathways, and interactions respectively.ResultsA total of 413 DEGs were identified in larval E. granulosus infected B cells, including 303 up- and 110 down-regulated genes. Notably, most DEGs related to inflammation and chemotaxis were significantly upregulated after infection. In line with these changes, significant expression upregulation of DEGs associated with fatty acid oxidation, lipid synthesis, lipolysis, lipid transport, and cholesterol biosynthesis, were observed in infected B cells. Co-expression network analysis showed an intimate interaction between these DEGs associated with immune and metabolism.ConclusionsThe present study revealed that the larval E. granulosus infection induces metabolic reprogramming of B cells, which provides a novel clue to clarify the immunoregulatory mechanism of B cells in parasitic infection.