Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation‐mediated neurotoxicity through inhibition of NF‐κB signalling pathway in Parkinson's disease model

Gan, Ping; Xia, Qiaofang; Hang, Guihua; Zhou, Yuxuan; Qian, Xiaojuan; Wang, Xiaomei; Ding, Liang

doi:10.1111/1440-1681.13052

Cited by 18 publications

(10 citation statements)

References 40 publications

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“…Therefore, it appears likely that the upregulation of pro-inflammatory cytokines seen in our study after pharmacological inhibition of cathepsin B, S, and L is also at least in part due to compensatory upregulation of various other cathepsins, such as cathepsin D, known to contribute to the development and maintenance of a pro-inflammatory M1-like phenotype [84,85]. In this context, knockout experiments in murine primary microglia cells have demonstrated that cathepsin D plays an important role in the activation of NF k B-mediated signaling pathways [86]. Another cathepsin family member warranting investigation in this context is cathepsin C. Strong expression of cathepsin C was detected in murine M1 macrophages and seems to be important for M1 polarization status.…”

Section: Discussionsupporting

confidence: 50%

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oelschlaegel

Sadan

Salpeter

et al. 2020

Cancers

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Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

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Section: Discussionsupporting

confidence: 50%

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oelschlaegel

Sadan

Salpeter

et al. 2020

Cancers

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“…In addition, CathD was also found to be up-regulated in the activated microglia (Takenouchi et al, 2011;Yelamanchili et al, 2011), the increased level of which can cause neuronal death (Amritraj et al, 2013). Our previous study reported that CathD was significantly up-regulated in MPTP-induced PD mice in vivo and in LPS-induced mice primary microglia in vitro, and that knockdown of CathD inhibited neuroinflammation and protected DA neurons from microglia-mediated neurotoxicity via inhibiting the activation of NF-kB signaling pathway (Gan et al, 2018). Therefore, CathD not only participates in the neuroinflammatory responses, but also trigger neurodegeneration and possibly development of neurodegenerative disorders including PD.…”

Section: Discussionmentioning

confidence: 97%

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

et al. 2020

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Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora flavescens, presents amounts of pharmacological properties including immunomodulation, anti-inflammation, anti-oxidation, and anti-virus. Recent studies tend to focus on its effects on neuroinflammation and neuroprotection in Parkinson's disease (PD) due to its profound anti-inflammatory effect. In this study, the neuroprotective and anti-neuroinflammatory effects of OMT were investigated in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-stimulated mice and 1-methyl-4-phenylpyridinium (MPP +)-induced mice primary microglia. Additionally, mice primary neuron-microglia cocultures and primary microglia infected with Cathepsin D (CathD)-overexpressed lentivirus were used to clarify whether the neuroprotective effect of OMT was through a CathDdependent pathway. Results showed that OMT dose-dependently alleviated MPTPinduced motor deficits and conferred significant dopamine (DA) neuroprotection against MPTP/MPP +-induced neurotoxicity. In addition, OMT inhibited MPTP/MPP +-induced microglia activation and the pro-inflammatory cytokines release. Further, OMT downregulated the expression of CathD, and inhibited the activation of the HMGB1/TLR4 signaling pathway as well as the nuclear translocation of NF-kB both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-kB signaling and OMT-produced neuroprotection in reconstituted neuron-microglia co-cultures. Our findings indicated that OMT conferred DA neuroprotection and attenuated microglial-mediated neuroinflammation through CathDdependent inhibition of HMGB1/TLR4/NF-kB signaling pathway. Our study supports a potential role for OMT in ameliorating PD, and proposes that OMT may be useful in the treatment of PD.

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“…Overloaded IL‐1β, IL‐6, and TNF‐α act on adjacent microglia to induce neuroinflammation and glia‐activated feedback loops which aggravates the production of neurotoxic molecules 34 . In addition, excessive NO inhibits mitochondrial cytochrome oxidase, which results in neuronal apoptosis 35 36 .…”

Section: Discussionmentioning

confidence: 99%

Imperatorin inhibits mitogen‐activated protein kinase and nuclear factor kappa‐B signaling pathways and alleviates neuroinflammation in ischemic stroke

Deng

Xue

et al. 2021

CNS Neurosci Ther

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Aims Microglia‐mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post‐stroke neuroinflammation is not fully understood. Methods Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT‐PCR, ELISA, and Western blot. The activation of MAPK and NF‐κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume. Results Imperatorin suppressed LPS‐induced activation of microglia and pro‐inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF‐κB pathways might contribute to the protective effects of imperatorin. Conclusions Imperatorin downregulated MAPK and NF‐κB signaling pathways and exerted anti‐inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke.

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Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation‐mediated neurotoxicity through inhibition of NF‐κB signalling pathway in Parkinson's disease model

Cited by 18 publications

References 40 publications

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

Imperatorin inhibits mitogen‐activated protein kinase and nuclear factor kappa‐B signaling pathways and alleviates neuroinflammation in ischemic stroke

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