論文 - 詳細
RRC ID | 67451 |
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著者 | Ni J, Zhao J, Zhang X, Reinheckel T, Turk V, Nakanishi H. |
タイトル | Cathepsin H deficiency decreases hypoxia-ischemia-induced hippocampal atrophy in neonatal mice through attenuated TLR3/IFN-β signaling. |
ジャーナル | J Neuroinflammation |
Abstract |
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. |
巻・号 | 18(1) |
ページ | 176 |
公開日 | 2021-8-10 |
DOI | 10.1186/s12974-021-02227-7 |
PII | 10.1186/s12974-021-02227-7 |
PMID | 34376208 |
PMC | PMC8353845 |
MeSH | Animals Atrophy / genetics Atrophy / metabolism Atrophy / pathology Cathepsin H / genetics* Cathepsin H / metabolism Cell Death / physiology Hippocampus / metabolism Hippocampus / pathology* Hypoxia-Ischemia, Brain / genetics* Hypoxia-Ischemia, Brain / metabolism Hypoxia-Ischemia, Brain / pathology Interferon-beta / genetics Interferon-beta / metabolism* Mice Mice, Knockout Microglia / metabolism Microglia / pathology Signal Transduction / physiology Toll-Like Receptor 3 / genetics Toll-Like Receptor 3 / metabolism* |
IF | 5.793 |
リソース情報 | |
ヒト・動物細胞 | MG6(RCB2403) |