Cathepsin H deficiency in mice induces excess Th1 cell activation and early-onset of EAE though impairment of toll-like receptor 3 cascade

Okada, Ryo; Zhang, Xinwen; Harada, Yuka; Wu, Zhou; Nakanishi, Hiroshi

doi:10.1007/s00011-018-1136-9

Cited by 12 publications

(10 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we speculated that CatH might have the same functions as CatB in the HI model, the present study has revealed their differential pathological roles. Our previous [11] and the present studies suggest that CatH is necessary for the activation of TLR3/IRF3 signaling and consequent secretion of IFN-β through proteolytic maturation and stabilization of TLR3. It is noted that TLR4 and TLR3 are differentially involved in the cerebral HI damage.…”

Section: Discussionsupporting

confidence: 71%

“…CatH (EC 3.4.22.16) is a lysosomal cysteine protease with a unique aminopeptidase activity, and its expression level is increased in activated immune cells [ 10 , 11 ]. Recently, we have reported that CatH deficiency impaired toll-like receptor 3 (TLR3)-mediated activation of interferon regulatory factor 3 (IRF3) and consequent secretion of interferon-β (IFN-β) from dendritic cells [ 11 ]. Furthermore, there is increasing evidence that IFN-β secreted from microglia/macrophages has neuroprotective effects.…”

Section: Introductionmentioning

confidence: 99%

“…Glial scar formation prevents infiltration of peripheral inflammatory cells or molecules, whereas it can also be detrimental to neuronal recovery by constituting a physical and biochemical barrier that inhibits axonal regeneration [4,9]. CatH (EC 3.4.22.16) is a lysosomal cysteine protease with a unique aminopeptidase activity, and its expression level is increased in activated immune cells [10,11]. Recently, we have reported that CatH deficiency impaired toll-like receptor 3 (TLR3)-mediated activation of interferon regulatory factor 3 (IRF3) and consequent secretion of interferon-β (IFN-β) from dendritic cells [11].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cathepsin H deficiency decreases hypoxia-ischemia-induced hippocampal atrophy in neonatal mice through attenuated TLR3/IFN-β signaling

Zhao

Zhang

et al. 2021

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

Background Cathepsin H (CatH) is a lysosomal cysteine protease with a unique aminopeptidase activity. Its expression level is increased in activated immune cells including dendritic cells, macrophages, and microglia. We have previously reported that CatH deficiency impairs toll-like receptor 3 (TLR3)-mediated activation of interferon regulatory factor 3 (IRF3), and the subsequent secretion of interferon (IFN)-β from dendritic cells. Furthermore, there is increasing evidence that IFN-β secreted from microglia/macrophages has neuroprotective effects. These observations prompted further investigation into the effects of CatH deficiency on neuropathological changes. Methods In this study, neuropathological changes were examined using histochemical staining (both hematoxylin-eosin (H&E) and Nissl) of the hippocampus of wild-type (WT) and CatH-deficient (CatH−/−) mice after hypoxia-ischemia (HI). The density and the localization of CatH and TLR3 were examined by immunofluorescent staining. CatH processing in microglia was assayed by pulse-chase experiments, while immunoblotting was used to examine TLR3 expression and IRF3 activation in microglia/macrophages in the presence of poly(I:C). Microglial cell death was examined by fluorescence-activated cell sorting (FACS), and primary astrocyte proliferation in the presence of IFN-β was examined using scratch wound assay. Results WT mice displayed severe atrophy in association with neuronal death and moderate astrogliosis in the hippocampus following neonatal HI. Somewhat surprisingly, CatH−/− mice showed marked neuronal death without severe atrophy in the hippocampus following HI. Furthermore, there was notable microglia/macrophages cell death and strong astrogliosis in the hippocampus. The TLR3 and phosphorylated IRF3 expression level in the hippocampus or splenocytes (mainly splenic macrophages); from CatH−/− mice was lower than in WT mice. In vitro experiments demonstrated that recombinant IFN-β suppressed HI-induced microglial cell death and astrocyte proliferation. Conclusion These observations suggest that CatH plays a critical role in the proteolytic maturation and stabilization of TLR3, which is necessary for IFN-β production. Therefore, impaired TLR3/IFN-β signaling resulting from CatH deficiency may induce microglial cell death after activation and astrogliosis/glial scar formation in the hippocampus following HI injury, leading to suppression of hippocampal atrophy.

show abstract

Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cathepsin H deficiency decreases hypoxia-ischemia-induced hippocampal atrophy in neonatal mice through attenuated TLR3/IFN-β signaling

Zhao

Zhang

et al. 2021

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

show abstract

“…CTSH encodes cathepsin H, which is a member of the papain-like cysteine proteases that are primarily involved in endolysosomal protein degradation, activation of other proteases ( 21 ), as well as major histocompatibility complex class II antigen presentation. Although CTSH -null mice do not demonstrate gross developmental defects ( 22 ), CTSH was associated with autoimmunity in mouse models and humans including experimental autoimmune encephalomyelitis ( 23 ) and T1D ( 24 ). CTSH is expressed in pancreatic beta cells and antigen-presenting cells but not in T cells ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation

Stefan-Lifshitz

Tomer

2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

“…TLR3/MyD88 independent pathway promotes the secretion of IL-27 to suppress the mature of Th17 cells ( 69 ). The lack of Cathepsin H damages TLR3-mediated IRF3 activation, inhibits IFN-β secretion from DCs and promotes Th1 cell differentiation ( 70 ). Activation of TLR3 in astrocytes induces the expression of neuroprotective mediators, including anti-inflammatory cytokines IL-9, IL-10, and IL-11, and down-regulates the secretion of pro-inflammatory cytokines IL-12 and IL-23, and inhibits gliosis and promotes neuronal survival, angiogenesis, and myelin regeneration ( 71 , 72 ).…”

Section: Role Of Tlrs In Neuroimmune Diseasesmentioning

confidence: 99%

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

Liu

Han

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

Toll-like receptors (TLRs) are a class of proteins playing a key role in innate and adaptive immune responses. TLRs are involved in the development and progression of neuroimmune diseases via initiating inflammatory responses. Thus, targeting TLRs signaling pathway may be considered as a potential therapy for neuroimmune diseases. However, the role of TLRs is elusive and complex in neuroimmune diseases. In addition to the inadequate immune response of TLRs inhibitors in the experiments, the recent studies also demonstrated that partial activation of TLRs is conducive to the production of anti-inflammatory factors and nervous system repair. Exploring the mechanism of TLRs in neuroimmune diseases and combining with developing the emerging drug may conquer neuroimmune diseases in the future. Herein, we provide an overview of the role of TLRs in several neuroimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barré syndrome and myasthenia gravis. Emerging difficulties and potential solutions in clinical application of TLRs inhibitors will also be discussed.

show abstract

Cathepsin H deficiency in mice induces excess Th1 cell activation and early-onset of EAE though impairment of toll-like receptor 3 cascade

Cited by 12 publications

References 7 publications

Cathepsin H deficiency decreases hypoxia-ischemia-induced hippocampal atrophy in neonatal mice through attenuated TLR3/IFN-β signaling

Cathepsin H deficiency decreases hypoxia-ischemia-induced hippocampal atrophy in neonatal mice through attenuated TLR3/IFN-β signaling

Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

Contact Info

Product

Resources

About