Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription

Guo, Bingxin1,2; Shi, Xing1,2; Jiang, Qiong1,2; Pan, Yuanwei3; Yang, Yuqiong1,2,4; Liu, Yuanyuan5; Chen, Shuyu1,2; Zhu, Wenjiao1,2; Ren, Laibin1,2; Liang, Ruifang1,2,5; Chen, Xue1,2; Xu, Haizhao1,2; Wei, Laiyou1,2; Lin, Yongjian1,2,6; Wang, Jinyong1,2; Qiu, Chen1,2; Zhou, Haibo6; Rao, Lang3; Wang, Lingwei1,2; Chen, Rongchang1,2; Chen, Shanze1,2

2024-10-01

10.1002/advs.202405318

ADVANCED SCIENCE   影响因子和分区

2198-3844

["Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition alleviated various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, an elevated expression of immunoproteasome subunits LMP2 and LMP7 in the macrophages isolated from mouse with LPS/Elastase-induced emphysema and polarized macrophages in vitro is observed. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated COPD-associated airway inflammation and improved lung function in mice by suppressing macrophage polarization. Additionally, ONX-0914 capsulated in PLGA nanoparticles exhibited more pronounced therapeutic effect on COPD than naked ONX-0914 by targeting immunoproteasome in polarized macrophages. Mechanistically, ONX-0914 activated autophagy and endoplasmic reticulum (ER) stress are not attribute to the ONX-0914 mediated suppression of macrophage polarization. Intriguingly, ONX-0914 inhibited M1 polarization through the nuclear factor erythroid 2-related factor-1 (NRF1) and NRF2-P62 axis, while the suppression of M2 polarization is regulated by inhibiting the transcription of interferon regulatory factor 4 (IRF4). In summary, the findings suggest that targeting immunoproteasome in macrophages holds promise as a therapeutic strategy for COPD.","This study performs immunoproteasome inhibitor ONX-0194 effectively prevents the development of emphysema by modulating macrophage activation. Mechanistically, ONX-0194 mitigates macrophage inflammation, involving the activation of the NRF1 and NRF2-P62 axis in M1 polarization, and regulation of IRF4 in M2 polarization. These findings strongly suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic approach for COPD. image"]

emphysema immunoproteasome IRF4 macrophage polarization NRF1/2-P62

SCI

英语

第一 ; 通讯

National Key Technologies Research and Development Program of China["2022YFF0710800","2022YFF0710802"] ; National Key R&D Program of China["82470033","3210074","81803183","32100914","82200080"] ; National Natural Science Foundation of China["2021A1515010478","2214050008970"] ; Natural Science Foundation of Guangdong province, China["A2303030","B2302041"] ; Shenzhen Medical Research fund["JCYJ20210324114400002","KCXFZ202002011008256"] ; Shenzhen Science Technology and Innovative Commission (SZSTI)[C2302001] ; Shenzhen Medical Academy of Research and Translation[JCYJ20210324114400001]

Chemistry ; Science & Technology - Other Topics ; Materials Science

Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:001324204700001

WILEY

Web of Science

1.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Peoples Hosp, Dept Pulm & Crit Care Med,Shenzhen Inst Resp Dis, Shenzhen 518055, Peoples R China
2.Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Peoples R China
3.Inst Chem Biol, Shenzhen Bay Lab, Shenzhen 518132, Peoples R China
4.Guangzhou Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis, State Key Lab Resp Dis,Guangzhou Inst Resp Hlth, Guangzhou 510150, Peoples R China
5.Jinan Univ, Clin Med Coll 2, Postdoctoral Sci Res Stn Basic Med, Dept Resp Dis & Crit Care Unit,Shenzhen Inst Resp, Guangzhou 510632, Peoples R China
6.Jinan Univ, Coll Pharm, Guangzhou 510632, Guangdong, Peoples R China

Guo, Bingxin,Shi, Xing,Jiang, Qiong,et al. Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription[J]. ADVANCED SCIENCE,2024.

Guo, Bingxin.,Shi, Xing.,Jiang, Qiong.,Pan, Yuanwei.,Yang, Yuqiong.,...&Chen, Shanze.(2024).Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription.ADVANCED SCIENCE.

Guo, Bingxin,et al."Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription".ADVANCED SCIENCE (2024).