Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity-Reference-Cited by-同舟云学术

Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Published:2014-11-21 Issue:6212 Volume:346 Page:1000-1003
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Fowler Benjamin J.¹²,Gelfand Bradley D.¹³⁴,Kim Younghee¹,Kerur Nagaraj¹,Tarallo Valeria¹⁵,Hirano Yoshio¹,Amarnath Shoba⁶,Fowler Daniel H.⁶,Radwan Marta⁷,Young Mark T.⁷,Pittman Keir⁸,Kubes Paul⁸,Agarwal Hitesh K.⁹,Parang Keykavous⁹,Hinton David R.¹⁰,Bastos-Carvalho Ana¹,Li Shengjian¹,Yasuma Tetsuhiro¹,Mizutani Takeshi¹,Yasuma Reo¹,Wright Charles¹,Ambati Jayakrishna¹²

Affiliation:

1. Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.

2. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.

3. Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA.

4. Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA.

5. Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy

6. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

7. School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.

8. Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

9. Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA.

10. Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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