RRC ID 67451
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)