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

Abstract:

: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-1β was strongly impaired. The expression of pro-IL-1β, 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-1β production, suggesting that targeting to PML could be used to treat NLRP3 inflammasome-associated diseases.

journal_name

Blood

journal_title

Blood

authors

Lo YH,Huang YW,Wu YH,Tsai CS,Lin YC,Mo ST,Kuo WC,Chuang YT,Jiang ST,Shih HM,Lai MZ

doi

10.1182/blood-2012-05-432104

subject

Has Abstract

pub_date

2013-04-18 00:00:00

pages

3185-94

issue

16

eissn

0006-4971

issn

1528-0020

pii

blood-2012-05-432104

journal_volume

121

pub_type

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