Sulforaphane activates anti-inflammatory microglia, modulating stress resilience associated with BDNF transcription

Tang, Rui; Cao, Qianqian; Hu, Sheng-Wei; He, Lujuan; Du, Pengfei; Chen, Gang; Fu, Rao; Xiao, Fei; Sun, Yirong; Zhang, Ji-Chun; Qi, Qi

doi:10.1038/s41401-021-00727-z

Cited by 22 publications

(19 citation statements)

References 60 publications

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“…Multiple lines of evidence suggest that the BDNF-TrkB signaling pathway plays a role in the pathophysiology of depression and the therapeutic mechanisms of antidepressants [ 38 – 46 ]. The activation of the anti-inflammatory phenotype of microglia reportedly coordinates the expression of various anti-inflammatory factors and increases BDNF expression, effecting stress resilience in mice [ 29 , 47 ]. Immunoblotting suggested that the levels of BDNF decreased in LPS-treated primary microglia: an outcome reversed with SFN (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, our study revealed that Nrf2 activates brain-derived neurotrophic factor (BDNF) and thus contributes to antidepressant-like effects on rodents [ 28 ]. Further, the activation of Nrf2 by SFN (Nrf2 activator) confers stress resilience through the activation of anti-inflammatory microglia, which are associated with BDNF upregulation [ 29 ]. Such findings suggest that Nrf2 may regulate the microglial anti-inflammatory phenotype through the initiation of TREM2 transcription and thus ameliorate depression-like behavior in mice.…”

Section: Introductionmentioning

confidence: 99%

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Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice

Zheng

Huang

et al. 2022

Transl Psychiatry

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The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice

Zheng

Huang

et al. 2022

Transl Psychiatry

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“…Sulforaphane has been previously shown to upregulate BDNF in BV2 microglia cell line (20). While we did not detect upregulation of BDNF after sulforaphane treatment in iMGLs of any individual, we noticed a significant upregulation of BDNF expression after clozapine and minocycline treatments in ST iMGLs (Figure 4f).…”

Section: Heterogeneous Response To Different Drug Treatments In Twins...mentioning

confidence: 48%

“…Minocycline is an antibiotic drug, which has been shown to inhibit microglial activation and synaptic pruning, and thus holds potential for alternative treatment for SCZ (15,17,18). Sulforaphane is an antioxidant, which can modulate inflammation-related depression-like behavior in rodents (19,20). Clozapine and minocycline have multiple targets, which are not all well-known, while sulforaphane mainly induces NF-E2-related factor-2 (NRF2) activation.…”

Section: Introductionmentioning

confidence: 99%

Genetic contribution to microglial activation in schizophrenia

Koistinaho

Koskuvi²,

Pörsti³

et al. 2022

Preprint

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Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Hyperactivation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes, such as AIF1, HLA-DRA and IL1β compared to healthy individuals. Microglia from affected twins had also reduced response to IL1β treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent GO terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of MHC class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have genetic aberrations related to inflammation response and extracellular matrix without contributing to microglia hyperactivation.

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“…A recent study shows that Nrf2 can bind to BDNF exon I promoter, resulting in BDNF transcription [ 25 , 51 ]. Furthermore, MeCP2 is a transcription repressor, which blocks BDNF transcription [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity

et al. 2022

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Mounting evidence suggests the key role of brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity of Parkinson’s disease (PD). Activation of NF-E2-related factor-2 (Nrf2) and inhibition of methyl CpG-binding protein 2 (MeCP2) can regulate BDNF upregulation. However, the regulation of BDNF by Nrf2 and MeCP2 in the PD pathogenesis has not been reported. Here, we revealed that Nrf2/MeCP2 coordinately regulated BDNF transcription, reversing the decreased levels of BDNF expression in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Repeated administration of sulforaphane (SFN, an Nrf2 activator) attenuated dopaminergic neurotoxicity in MPTP-treated mice through activation of BDNF and suppression of MeCP2 expression. Furthermore, intracerebroventricular injection of MeCP2-HDO, a DNA/RNA heteroduplex oligonucleotide (HDO) silencing MeCP2 expression, ameliorated dopaminergic neurotoxicity in MPTP-treated mice via activation of Nrf2 and BDNF expression. Moreover, we found decreased levels of Nrf2 and BDNF, and increased levels of MeCP2 protein expression in the striatum of patients with dementia with Lewy bodies (DLB). Interesting, there were correlations between BDNF and Nrf2 (or MeCP2) expression in the striatum from DLB patients. Therefore, it is likely that the activation of BDNF transcription by activation of Nrf2 and/or suppression of MeCP2 could be a new therapeutic approach for PD.

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Sulforaphane activates anti-inflammatory microglia, modulating stress resilience associated with BDNF transcription

Cited by 22 publications

References 60 publications

Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice

Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice

Genetic contribution to microglial activation in schizophrenia

Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity

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