Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway

Tripathi, Ashutosh; Whitehead, Carl; Surrao, Katelyn; Pillai, Ananya; Madeshiya, Amit Kumar; Li, Yong; Khodadadi, Hesam; Ahmed, Anthony O.; Turecki, Gustavo; Baban, Babak; Pillai, Anilkumar

doi:10.1038/s41380-021-01065-6

Cited by 37 publications

(28 citation statements)

References 123 publications

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“…This pathway has been reported in immune diseases, such as multiple sclerosis (Li et al, 2021), Ig A nephropathy, and Henoch-Schönlein purpura nephritis (Fang et al, 2021). Complement activation has been demonstrated in previous reports (Roy et al, 2020;Tripathi et al, 2021) to be associated with type I interferon, which was significantly activated in DM and DM-ILD (Zhang et al, 2019a;de Jesus et al, 2020). These reports combined with our findings suggest direct and/or indirect links between the two pathways implicated in DM-ILD pathogenesis.…”

Section: Discussionsupporting

confidence: 87%

Transcriptome Sequencing Identifies PLAUR as an Important Player in Patients With Dermatomyositis-Associated Interstitial Lung Disease

et al. 2021

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Dermatomyositis (DM), an inflammatory disorder, is often associated with interstitial lung disease (ILD). However, the underlying mechanism remains unclear. Our study performed RNA sequencing (RNA-seq) and integrative bioinformatics analysis of differentially expressed genes (DEGs) in patients with dermatomyositis-associated interstitial lung disease (DM-ILD) and healthy controls. A total of 2,018 DEGs were identified between DM-ILD and healthy blood samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that DEGs were mainly involved in immune- and inflammatory-related biological processes and pathways. Disease ontology (DO) enrichment analysis identified 35 candidate key genes involved in both skin and lung diseases. Meanwhile, a total of 886 differentially expressed alternative splicing (AS) events were found between DM-ILD and healthy blood samples. After overlapping DEGs with differential AS genes, the plasminogen activator and urokinase receptor (PLAUR) involved in immune-related biological processes and complement and coagulation cascades was screened and identified as the most important gene associated with DM-ILD. The protein–protein interaction (PPI) network revealed that PLAUR had interactions with multiple candidate key genes. Moreover, we observed that there were significantly more neutrophils and less naive B cells in DM-ILD samples than in healthy samples. And the expression of PLAUR was significantly positively correlated with the abundance of neutrophils. Significant higher abundance of PLAUR in DM-ILD patients than healthy controls was validated by RT-qPCR. In conclusion, we identified PLAUR as an important player in regulating DM-ILD by neutrophil-associated immune response. These findings enrich our understanding, which may benefit DM-ILD patients.

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Section: Discussionsupporting

confidence: 87%

Transcriptome Sequencing Identifies PLAUR as an Important Player in Patients With Dermatomyositis-Associated Interstitial Lung Disease

et al. 2021

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“…No statistical methods were used to predetermine sample sizes in the current study, but our sample sizes are similar to those reported in previous publications [ 24 , 25 ]. Data were presented as mean ± SEM.…”

Section: Methodsmentioning

confidence: 77%

“…Similarly, our earlier study found an increase in C3 mRNA levels in the prefrontal cortex (PFC) of depressed suicide subjects [ 23 ]. In addition, we found that inhibition of C3a signaling attenuates chronic stress-induced depressive-like behavior in mice [ 23 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

C1q deletion exacerbates stress-induced learned helplessness behavior and induces neuroinflammation in mice

et al. 2022

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Increased levels of pro-inflammatory cytokines have been reported in postmortem brain samples and in the blood of depressed subjects. However, the inflammatory pathways that lead to depressive-like symptoms are not well understood. Using the learned helplessness (LH) model of depression, we examined the role of C1q, the initiator of classical complement pathway in mediating stress-induced depressive-like behavior in mice. We observed no significant changes in social behavior, despair behavior, spatial memory, and aggressive behavior between the wild type (WT) and C1q knockout (KO) mice. However, C1q deletion exacerbated the inescapable electric foot shock-induced learned helplessness behavior in mice. We found significant reductions in C1q mRNA levels in the prefrontal cortex (PFC) of WT helpless mice as compared to the naïve mice. Increased levels of pro-inflammatory cytokines were found in the PFC of C1q KO mice. These findings suggest that classical complement pathway-mediated learned helplessness behavior is accompanied by neuroinflammatory changes under stressful conditions.

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“…In vivo, we observed that the IFN-β mRNA expression in the prefrontal cortex was signi cantly decreased in RST mice compared with control mice, However, the serum IFN-β level was enhanced in RST mice. Consistently, recent study reported that serum IFN-β levels was increased in chronic stress mice, and systemic blockade of type interferons signaling attenuated chronic stress-induced in ltration of macrophages into prefrontal cortex and behavioral abnormalities [40]. The reason behind the differing levels in the brain or serum in chronic restraint stress is not clear.…”

Section: Discussionmentioning

confidence: 93%

Therapeutic STING activation boosts microglia phagocytosis and ameliorates depression-like behaviors during chronic restraint stress

Zhai

Zhang

Tan

et al. 2021

Preprint

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Background The STING-TBK1-IRF3 signaling pathway involves in modulating host innate immunity, however, the potential role of STING signaling pathway in chronic restraint stress model has not been determined. The aim of this study is to explore the underlying role of STING signaling pathway in regulating neuroinflammation, as well as to evaluate the therapeutic potential of STING agonist during chronic restraint stress. Methods C57BL/6 mice were subjected to 14-day intermittent restraint stress. Sucrose preference, elevated plus maze and tail suspension tests were measured in chronic restraint stress mice. Expression levels of proinflammatory cytokines were tested by QT-PCR and Luminex cytokine assays. The fluorescence-labeled latex beads, flow cytometry and CD68 positive cell counts were utilized to evaluate phagocytic abilities of microglia. Then, the ability of intracerebroventricular injection of STING agonist, 2’3-cGAMP, to reverse the depression-like behaviors and inflammatory cytokines was examined. Results We found that the expression levels of STING, p-TBK1, and p-IRF3 were remarkably decreased in chronic restraint stress mice, which was associated with decreased IFN-β secretion. Moreover, the STING agonist, 2’3-cGAMP, significantly alleviated the neuroinflammation and ameliorated depression-like behavior which depends on the functional STING activation. Furthermore, 2’3-cGAMP promoted microglia phagocytosis through STING-dependent IFN-β release, which was essential for recovery from neuroinflammation during chronic restraint stress. Conclusions These findings demonstrate that STING signaling pathway is a critical mediator in regulating microglia phagocytosis and may serve as a novel therapeutic target for chronic stress-related psychiatric diseases.

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Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway

Cited by 37 publications

References 123 publications

Transcriptome Sequencing Identifies PLAUR as an Important Player in Patients With Dermatomyositis-Associated Interstitial Lung Disease

Transcriptome Sequencing Identifies PLAUR as an Important Player in Patients With Dermatomyositis-Associated Interstitial Lung Disease

C1q deletion exacerbates stress-induced learned helplessness behavior and induces neuroinflammation in mice

Therapeutic STING activation boosts microglia phagocytosis and ameliorates depression-like behaviors during chronic restraint stress

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