Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Details

• Alternative Title:
  Science
• Personal Author:
  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
• 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

  More +
• 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 ; 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
• Volume:
  346
• Issue:
  6212
• 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:
  [PDF - 1000.51 KB ]