Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

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

doi:10.1126/science.1256427

Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1000-1003
Number of pages	4
Journal	Science
Volume	346
Issue number	6212
DOIs	https://doi.org/10.1126/science.1256427
State	Published - Nov 21 2014
Externally published	Yes

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Fowler, B. J., Gelfand, B. D., Kim, Y., Kerur, N., Tarallo, V., Hirano, Y., Amarnath, S., Fowler, D. H., Radwan, M., Young, M. T., Pittman, K., Kubes, P., Agarwal, H. K., Parang, K., Hinton, D. R., Bastos-Carvalho, A., Li, S., Yasuma, T., Mizutani, T., ... Ambati, J. (2014). Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science, 346(6212), 1000-1003. https://doi.org/10.1126/science.1256427

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; Hinton, David R.; Bastos-Carvalho, Ana; Li, Shengjian; Yasuma, Tetsuhiro; Mizutani, Takeshi; Yasuma, Reo; Wright, Charles; Ambati, Jayakrishna.

In: Science, Vol. 346, No. 6212, 21.11.2014, p. 1000-1003.

Research output: Contribution to journal › Article › peer-review

Fowler, BJ, Gelfand, BD, Kim, Y, Kerur, N, Tarallo, V, Hirano, Y, Amarnath, S, Fowler, DH, Radwan, M, Young, MT, Pittman, K, Kubes, P, Agarwal, HK, Parang, K, Hinton, DR, Bastos-Carvalho, A, Li, S, Yasuma, T, Mizutani, T, Yasuma, R, Wright, C & Ambati, J 2014, 'Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity', Science, vol. 346, no. 6212, pp. 1000-1003. https://doi.org/10.1126/science.1256427

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 ; Hinton, David R. ; Bastos-Carvalho, Ana ; Li, Shengjian ; Yasuma, Tetsuhiro ; Mizutani, Takeshi ; Yasuma, Reo ; Wright, Charles ; Ambati, Jayakrishna. / Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. In: Science. 2014 ; Vol. 346, No. 6212. pp. 1000-1003.

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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.",

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

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AU - Hirano, Yoshio

AU - Amarnath, Shoba

AU - Fowler, Daniel H.

AU - Radwan, Marta

AU - Young, Mark T.

AU - Pittman, Keir

AU - Kubes, Paul

AU - Agarwal, Hitesh K.

AU - Parang, Keykavous

AU - Hinton, David R.

AU - Bastos-Carvalho, Ana

AU - Li, Shengjian

AU - Yasuma, Tetsuhiro

AU - Mizutani, Takeshi

AU - Yasuma, Reo

AU - Wright, Charles

AU - Ambati, Jayakrishna

PY - 2014/11/21

Y1 - 2014/11/21

N2 - 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.

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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

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