Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Fowler, Benjamin J.; Gelfand, Bradley D.; Kim, Younghee; Kerur, Nagaraj; Tarallo, Valeria; Hirano, Yoshio; Amarnath, Shoba; Fowler, Daniel H.; Radwan, Marta; Young, Mark T.; Pittman, Keir; Kubes, Paul; Agarwal, Hitesh K.; Parang, Keykavous A.; Hinton, David R.; Bastos-Carvalho, Ana; Li, Shengjian; Yasuma, Tetsuhiro; Mizutani, Takeshi; Yasuma, Reo; Wright, Charles; Ambati, Jayakrishna

doi:10.1126/science.1261754

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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Nov 21 2014
By Fowler, Benjamin J. ; Gelfand, Bradley D. ; Kim, Younghee ; ...
http://dx.doi.org/10.1126/science.1261754
Source: Science. 346(6212):1000-1003.

[PDF-1000.51 KB]

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Details:

Alternative Title:

Science
Personal Author:

Fowler, Benjamin J. ; Gelfand, Bradley D. ; Kim, Younghee ; Kerur, Nagaraj ; Tarallo, Valeria ; ... More +

Fowler, Benjamin J. ; Gelfand, Bradley D. ; Kim, Younghee ; Kerur, Nagaraj ; Tarallo, Valeria ; Hirano, Yoshio ; Amarnath, Shoba ; Fowler, Daniel H. ; Radwan, Marta ; Young, Mark T. ; Pittman, Keir ; Kubes, Paul ; Agarwal, Hitesh K. ; Parang, Keykavous A. ; Hinton, David R. ; Bastos-Carvalho, Ana ; Li, Shengjian ; Yasuma, Tetsuhiro ; Mizutani, Takeshi ; Yasuma, Reo ; Wright, Charles ; Ambati, Jayakrishna Less -
Description:

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.
Subjects:

[+]

Alu Elements Animals Anti-Inflammatory Agents, Non-Steroidal Apoptosis Article Carrier Proteins Caspase 1 Choroidal Neovascularization Disease Models, Animal Geographic Atrophy Graft Vs Host Disease Hepatitis Inflammasomes Liver Mice Receptors, Purinergic P2X7 Retinal Pigment Epithelium Reverse Transcriptase Inhibitors
Source:

Science. 346(6212):1000-1003.
Pubmed ID:

25414314
Pubmed Central ID:

PMC4274127
Document Type:

Journal Article
Funding:

BB/J017345/1/Biotechnology and Biological Sciences Research Council/United Kingdom ; DP1 GM114862/GM/NIGMS NIH HHS/United States ; DP1GM114862/DP/NCCDPHP CDC HHS/United States ; K99 EY024336/EY/NEI NIH HHS/United States ; K99EY024336/EY/NEI NIH HHS/United States ; ... More +

BB/J017345/1/Biotechnology and Biological Sciences Research Council/United Kingdom ; DP1 GM114862/GM/NIGMS NIH HHS/United States ; DP1GM114862/DP/NCCDPHP CDC HHS/United States ; K99 EY024336/EY/NEI NIH HHS/United States ; K99EY024336/EY/NEI NIH HHS/United States ; P30EY003040/EY/NEI NIH HHS/United States ; R01 EY018350/EY/NEI NIH HHS/United States ; R01 EY018836/EY/NEI NIH HHS/United States ; R01 EY020672/EY/NEI NIH HHS/United States ; R01 EY022238/EY/NEI NIH HHS/United States ; R01 EY024068/EY/NEI NIH HHS/United States ; R01EY001545/EY/NEI NIH HHS/United States ; R01EY018350/EY/NEI NIH HHS/United States ; R01EY018836/EY/NEI NIH HHS/United States ; R01EY020672/EY/NEI NIH HHS/United States ; R01EY022238/EY/NEI NIH HHS/United States ; R01EY024068/EY/NEI NIH HHS/United States ; T32HL091812/HL/NHLBI NIH HHS/United States ; TL1 RR033172/RR/NCRR NIH HHS/United States ; TL1 TR000115/TR/NCATS NIH HHS/United States ; UL1 RR033173/RR/NCRR NIH HHS/United States ; UL1 TR000117/TR/NCATS NIH HHS/United States ; UL1RR033173/RR/NCRR NIH HHS/United States Less -
Collection(s):

CDC Public Access
Main Document Checksum:

[+]

urn:sha256:6c220d262e99c34653e71763bc015c3c218c22756a7e8eb05a119147e043bac9
Download URL:

https://stacks.cdc.gov/view/cdc/30208/cdc_30208_DS1.pdf
File Type:

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	NIHMS649205-supplement-Supplementary_File.pdf	pdf
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