https://scholars.lib.ntu.edu.tw/handle/123456789/631884
標題: | Gouty arthritis involves impairment of autophagic degradation via cathepsin D inactivation-mediated lysosomal dysfunction that promotes apoptosis in macrophages | 作者: | YU-HSUAN CHEN Chen, Wei-Yu CHIA-LI YU Tsai, Chang-Youh SONG-CHOU HSIEH |
關鍵字: | Acute gouty arthritis; Autophagy-lysosome pathway perturbation; Chronic gouty arthritis; Monosodium urate crystals; Synovial fluid mononuclear cells; Synovial tissues | 公開日期: | 八月-2023 | 卷: | 1869 | 期: | 6 | 起(迄)頁: | 166703 | 來源出版物: | Biochimica et biophysica acta. Molecular basis of disease | 摘要: | This study examined autophagy-lysosome pathway (ALP) perturbations in synovial monocytes/macrophages from patients with gouty arthritis (GA) and the associations of ALP perturbations with cell death. Synovial fluid mononuclear cells (SFMCs) and synovial tissues (STs) from patients with GA, as well as monosodium urate (MSU) crystal-exposed macrophages, underwent immunoblotting, quantitative polymerase chain reaction, and immunofluorescence analyses of markers linked to the ALP (microtubule-associated protein 1 light chain 3B [LC3B], p62, cathepsin D [CTSD], and lysosome-associated membrane protein 2 [LAMP2]) and cell death (caspase-3). GA STs underwent immunohistochemistry and immunofluorescence analyses to determine the distributions of LC3B-positive autophagosomes and macrophages. GA SFMCs and STs exhibited impaired autophagic degradation, indicated by elevated levels of LC3B and p62, along with CTSD upregulation and caspase-3 activation. Macrophages from GA STs exhibited significant accumulation of LC3B-positive autophagosomes. The temporal effects of MSU crystals on the ALP and the associations of these effects with cell death were investigated using a macrophage model of GA. MSU crystal-exposed macrophages exhibited early (2 h) autophagosome formation but later (6-24 h) autophagic flux impairment, demonstrated by p62 accumulation, lysosomal inhibitor failure to increase LC3B accumulation, and LC3B colocalization with p62. These macrophages exhibited autophagic flux impairment because of CTSD inactivation-mediated lysosomal dysfunction, which caused immature CTSD to accumulate within damaged LAMP2-positive lysosomes. This accumulation coincided with caspase-3-dependent cell death (24 h) that was unaffected by CTSD inhibition. These findings indicate that GA involves MSU crystal-induced impairment of autophagic degradation via CTSD inactivation-mediated lysosomal dysfunction, which promotes apoptosis in macrophages. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/631884 | ISSN: | 09254439 | DOI: | 10.1016/j.bbadis.2023.166703 |
顯示於: | 醫學系 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。