Selective inhibition of the NLRP3 inflammasome by targeting to promyelocytic leukemia protein in mouse and human

被引：41

作者：

Lo, Yu-Hsun ^{[1
]}

Huang, Yu-Wen ^{[1
]}

Wu, Yung-Hsuan ^{[1
,2
]}

Tsai, Chi-Shan ^{[1
]}

Lin, Yu-Chuan ^{[1
]}

Mo, Shu-Ting ^{[1
]}

Kuo, Wen-Chih ^{[1
]}

Chuang, Ya-Ting ^{[1
]}

Jiang, Si-Tse ^{[3
]}

Shih, Hsiu-Ming ^{[4
]}

Lai, Ming-Zong ^{[1
,2
,5
]}

机构：

[1] Acad Sinica, Inst Mol Biol, Taipei 11529, Taiwan

[2] Natl Yang Ming Univ, Grad Inst Microbiol & Immunol, Taipei 112, Taiwan

[3] Natl Appl Res Labs, Natl Lab Anim Ctr, Tainan, Taiwan

[4] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan

[5] Natl Taiwan Univ, Grad Inst Immunol, Sch Med, Taipei 10764, Taiwan

来源：

BLOOD | 2013年 / 121卷 / 16期

关键词：

PML NUCLEAR-BODIES; CYTOPLASMIC PML; ACTIVATION; APOPTOSIS; DAXX;

D O I：

10.1182/blood-2012-05-432104

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The functional activities of the tumor suppressor promyelocytic leukemia protein (PML) are mostly associated with its nuclear location. In the present study, we discovered an unexpected role of PML in NLRP3 inflammasome activation. In PML-deficient macrophages, the production of IL-1 beta was strongly impaired. The expression of pro-IL-1 beta, NLRP3, ASC, and procaspase-1 was not affected in Pml(-/-) macrophages. PML deficiency selectively reduced the processing of procaspase-1. We further showed that PML is required for the assembly of the NLRP3 inflammasome in reconstitution experiment. All PML isoforms were capable of stimulating NLRP3 inflammasome activation. In Pml(-/-) macrophages, the generation of reactive oxygen species and release of mitochondrial DNA were decreased. The involvement of PML in inflammasome activation constitutes an important activity of PML and reveals a new mechanism underlying the inflammasome activation. In addition, downregulation of PML by arsenic trioxide suppressed monosodium urate (MSU)-induced IL-1 beta production, suggesting that targeting to PML could be used to treat NLRP3 inflammasome-associated diseases.

引用

页码：3185 / 3194

页数：10

共 44 条

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