Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

被引：180

作者：

Fowler, Benjamin J. ^{[1
,2
]}

Gelfand, Bradley D. ^{[1
,3
,4
]}

Kim, Younghee ^{[1
]}

Kerur, Nagaraj ^{[1
]}

Tarallo, Valeria ^{[1
,5
]}

Hirano, Yoshio ^{[1
]}

Amarnath, Shoba ^{[6
]}

Fowler, Daniel H. ^{[6
]}

Radwan, Marta ^{[7
]}

Young, Mark T. ^{[7
]}

Pittman, Keir ^{[8
]}

Kubes, Paul ^{[8
]}

Agarwal, Hitesh K. ^{[9
]}

Parang, Keykavous ^{[9
]}

Hinton, David R. ^{[10
,11
]}

Bastos-Carvalho, Ana ^{[1
]}

Li, Shengjian ^{[1
]}

Yasuma, Tetsuhiro ^{[1
]}

Mizutani, Takeshi ^{[1
]}

Yasuma, Reo ^{[1
]}

Wright, Charles ^{[1
]}

Ambati, Jayakrishna ^{[1
,2
]}

机构：

[1] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40536 USA

[2] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Microbiol Immunol & Human Genet, Lexington, KY 40536 USA

[4] Univ Kentucky, Dept Biomed Engn, Lexington, KY 40536 USA

[5] CNR, Inst Genet & Biophys, Angiogenesis Lab, I-80125 Naples, Italy

[6] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA

[7] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales

[8] Univ Calgary, Immunol Res Grp, Calgary, AB T2N 4N1, Canada

[9] Chapman Univ, Sch Pharm, Irvine, CA 92618 USA

[10] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

[11] Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA

来源：

SCIENCE | 2014年 / 346卷 / 6212期

基金：

英国生物技术与生命科学研究理事会;

关键词：

VERSUS-HOST-DISEASE; P2X(7) RECEPTOR; MACULAR DEGENERATION; INFLAMMASOME ACTIVATION; CASPASE-1; ACTIVATION; NLRP3; INFLAMMASOME; P2X7; RECEPTOR; ATP RELEASE; INTERLEUKIN-18; PATHOGENESIS;

D O I：

10.1126/science.1261754

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.

引用

页码：1000 / 1003

页数：4

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