title: Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA. Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Shoba
authors.initials: S
authors.lastname: Amarnath
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Radwan
authors.affiliation: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Young
authors.affiliation: Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Keir
authors.initials: K
authors.lastname: Pittman
authors.affiliation: Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.affiliation: Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.affiliation: Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.affiliation: Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Bastos-Carvalho
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Reo
authors.initials: R
authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. jamba2@email.uky.edu.
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D020087:Alu Elements; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000188:drug therapy; D004195:Disease Models, Animal; D057092:Geographic Atrophy / Q000188:drug therapy; D006086:Graft vs Host Disease / Q000188:drug therapy; D006505:Hepatitis / Q000188:drug therapy; D058847:Inflammasomes / Q000187:drug effects*; D008099:Liver / Q000187:drug effects; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D058486:Receptors, Purinergic P2X7; D018894:Reverse Transcriptase Inhibitors; D020170:Caspase 1