DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88

Valeria Tarallo; Yoshio Hirano; Bradley D. Gelfand; Sami Dridi; Nagaraj Kerur; Younghee Kim; Won Gil Cho; Hiroki Kaneko; Benjamin J. Fowler; Sasha Bogdanovich; Romulo J.C. Albuquerque; William W. Hauswirth; Vince A. Chiodo; Jennifer F. Kugel; James A. Goodrich; Steven L. Ponicsan; Gautam Chaudhuri; Michael P. Murphy; Joshua L. Dunaief; Balamurali K. Ambati; Yuichiro Ogura; Jae Wook Yoo; Dong Ki Lee; Patrick Provost; David R. Hinton; Gabriel Núñez; Judit Z. Baffi; Mark E. Kleinman; Jayakrishna Ambati

doi:10.1016/j.cell.2012.03.036

DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88

Valeria Tarallo, Yoshio Hirano, Bradley D. Gelfand, Sami Dridi, Nagaraj Kerur, Younghee Kim, Won Gil Cho, Hiroki Kaneko, Benjamin J. Fowler, Sasha Bogdanovich, Romulo J.C. Albuquerque, William W. Hauswirth, Vince A. Chiodo, Jennifer F. Kugel, James A. Goodrich, Steven L. Ponicsan, Gautam Chaudhuri, Michael P. Murphy, Joshua L. Dunaief, Balamurali K. AmbatiYuichiro Ogura, Jae Wook Yoo, Dong Ki Lee, Patrick Provost, David R. Hinton, Gabriel Núñez, Judit Z. Baffi, Mark E. Kleinman, Jayakrishna Ambati^*

^*Corresponding author for this work

Center for Genetic Medicine

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

525 Scopus citations

Abstract

Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.

Original language	English (US)
Pages (from-to)	847-859
Number of pages	13
Journal	Cell
Volume	149
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2012.03.036
State	Published - May 11 2012

Funding

We thank S. Akira, Z. Chen, M. Chrenek, J. Garcia-Perez, T. Heidmann, and J.V. Moran for providing mice, reagents, or tissues; R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, G.R. Pattison, and C. Spee for technical assistance; and S. Bondada, M.E. Boulton, R.A. Brekken, R. Kannan, K. Karik\u00F3, T.S. Khurana, R. Mohan, M.L. Peterson, V. Rangnekar, A. Sinai, A.M. Rao, G.S. Rao, and K. Ambati for discussions. J.A. was supported by NEI/NIH grants R01EY018350, R01EY018836, R01EY020672, R01EY022238, R21EY019778, and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Senior Scientist Investigator Award (Research to Prevent Blindness, RPB); J.Z.B. by NIH K08EY021521, International Retinal Research Foundation, and American Health Assistance Foundation; M.E.K. by NIH K08EY021757; B.J.F., S.B., and M.E.K. by NIH T32HL091812 and UL1RR033173; G.N. by NIH R01AI063331 and R01AR052756; Y.H. by Alcon Japan Research award; W.W.H. by NIH P30EY021721; B.K.A. by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense; D.R.H. by NIH P30EY003040 and R01EY001545; J.F.K. and J.A.G. by NIH R01GM068414; J.W.Y. and D.-k.L. by Global Research Laboratory grant from MEST, Korea. Departmental unrestricted grants from RPB supported J.A. and W.W.H. University of Kentucky Physician Scientist Awards supported J.Z.B. and M.E.K. P.P. is a Senior Scholar from the Fonds de la Recherche en Sant\u00E9 du Qu\u00E9bec (FRSQ). Several authors are named as inventors on patent applications filed by their universities relating to described technologies. V.T., Y.H., B.D.G., S.D., Y.K., W.G.C., J.Z.B., H.K., N.K., B.J.F., S.B., and M.E.K. performed experiments. W.W.H., V.A.C, S.L.P., J.F.K., J.A.G., M.P.M., J.W.Y., D.-k.L, D.R.H., P.P., and G.N. provided reagents. J.A. conceived and directed the project and wrote the paper with assistance from B.K.A., B.J.F., and B.D.G. All authors had the opportunity to discuss the results and comment on the manuscript.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2012.03.036

Cite this

Tarallo, V., Hirano, Y., Gelfand, B. D., Dridi, S., Kerur, N., Kim, Y., Cho, W. G., Kaneko, H., Fowler, B. J., Bogdanovich, S., Albuquerque, R. J. C., Hauswirth, W. W., Chiodo, V. A., Kugel, J. F., Goodrich, J. A., Ponicsan, S. L., Chaudhuri, G., Murphy, M. P., Dunaief, J. L., ... Ambati, J. (2012). DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell, 149(4), 847-859. https://doi.org/10.1016/j.cell.2012.03.036

@article{7eeac89b13e84f408d534770db15e9f4,

title = "DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88",

abstract = "Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.",

author = "Valeria Tarallo and Yoshio Hirano and Gelfand, {Bradley D.} and Sami Dridi and Nagaraj Kerur and Younghee Kim and Cho, {Won Gil} and Hiroki Kaneko and Fowler, {Benjamin J.} and Sasha Bogdanovich and Albuquerque, {Romulo J.C.} and Hauswirth, {William W.} and Chiodo, {Vince A.} and Kugel, {Jennifer F.} and Goodrich, {James A.} and Ponicsan, {Steven L.} and Gautam Chaudhuri and Murphy, {Michael P.} and Dunaief, {Joshua L.} and Ambati, {Balamurali K.} and Yuichiro Ogura and Yoo, {Jae Wook} and Lee, {Dong Ki} and Patrick Provost and Hinton, {David R.} and Gabriel N{\'u}{\~n}ez and Baffi, {Judit Z.} and Kleinman, {Mark E.} and Jayakrishna Ambati",

note = "Funding Information: We thank S. Akira, Z. Chen, M. Chrenek, J. Garcia-Perez, T. Heidmann, and J.V. Moran for providing mice, reagents, or tissues; R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, G.R. Pattison, and C. Spee for technical assistance; and S. Bondada, M.E. Boulton, R.A. Brekken, R. Kannan, K. Karik{\'o}, T.S. Khurana, R. Mohan, M.L. Peterson, V. Rangnekar, A. Sinai, A.M. Rao, G.S. Rao, and K. Ambati for discussions. J.A. was supported by NEI/NIH grants R01EY018350, R01EY018836, R01EY020672, R01EY022238, R21EY019778, and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Senior Scientist Investigator Award (Research to Prevent Blindness, RPB); J.Z.B. by NIH K08EY021521, International Retinal Research Foundation, and American Health Assistance Foundation; M.E.K. by NIH K08EY021757; B.J.F., S.B., and M.E.K. by NIH T32HL091812 and UL1RR033173; G.N. by NIH R01AI063331 and R01AR052756; Y.H. by Alcon Japan Research award; W.W.H. by NIH P30EY021721; B.K.A. by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense; D.R.H. by NIH P30EY003040 and R01EY001545; J.F.K. and J.A.G. by NIH R01GM068414; J.W.Y. and D.-k.L. by Global Research Laboratory grant from MEST, Korea. Departmental unrestricted grants from RPB supported J.A. and W.W.H. University of Kentucky Physician Scientist Awards supported J.Z.B. and M.E.K. P.P. is a Senior Scholar from the Fonds de la Recherche en Sant{\'e} du Qu{\'e}bec (FRSQ). Several authors are named as inventors on patent applications filed by their universities relating to described technologies. V.T., Y.H., B.D.G., S.D., Y.K., W.G.C., J.Z.B., H.K., N.K., B.J.F., S.B., and M.E.K. performed experiments. W.W.H., V.A.C, S.L.P., J.F.K., J.A.G., M.P.M., J.W.Y., D.-k.L, D.R.H., P.P., and G.N. provided reagents. J.A. conceived and directed the project and wrote the paper with assistance from B.K.A., B.J.F., and B.D.G. All authors had the opportunity to discuss the results and comment on the manuscript. ",

year = "2012",

month = may,

day = "11",

doi = "10.1016/j.cell.2012.03.036",

language = "English (US)",

volume = "149",

pages = "847--859",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "4",

}

Tarallo, V, Hirano, Y, Gelfand, BD, Dridi, S, Kerur, N, Kim, Y, Cho, WG, Kaneko, H, Fowler, BJ, Bogdanovich, S, Albuquerque, RJC, Hauswirth, WW, Chiodo, VA, Kugel, JF, Goodrich, JA, Ponicsan, SL, Chaudhuri, G, Murphy, MP, Dunaief, JL, Ambati, BK, Ogura, Y, Yoo, JW, Lee, DK, Provost, P, Hinton, DR, Núñez, G, Baffi, JZ, Kleinman, ME & Ambati, J 2012, 'DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88', Cell, vol. 149, no. 4, pp. 847-859. https://doi.org/10.1016/j.cell.2012.03.036

TY - JOUR

T1 - DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88

AU - Tarallo, Valeria

AU - Hirano, Yoshio

AU - Gelfand, Bradley D.

AU - Dridi, Sami

AU - Kerur, Nagaraj

AU - Kim, Younghee

AU - Cho, Won Gil

AU - Kaneko, Hiroki

AU - Fowler, Benjamin J.

AU - Bogdanovich, Sasha

AU - Albuquerque, Romulo J.C.

AU - Hauswirth, William W.

AU - Chiodo, Vince A.

AU - Kugel, Jennifer F.

AU - Goodrich, James A.

AU - Ponicsan, Steven L.

AU - Chaudhuri, Gautam

AU - Murphy, Michael P.

AU - Dunaief, Joshua L.

AU - Ambati, Balamurali K.

AU - Ogura, Yuichiro

AU - Yoo, Jae Wook

AU - Lee, Dong Ki

AU - Provost, Patrick

AU - Hinton, David R.

AU - Núñez, Gabriel

AU - Baffi, Judit Z.

AU - Kleinman, Mark E.

AU - Ambati, Jayakrishna

N1 - Funding Information: We thank S. Akira, Z. Chen, M. Chrenek, J. Garcia-Perez, T. Heidmann, and J.V. Moran for providing mice, reagents, or tissues; R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, G.R. Pattison, and C. Spee for technical assistance; and S. Bondada, M.E. Boulton, R.A. Brekken, R. Kannan, K. Karikó, T.S. Khurana, R. Mohan, M.L. Peterson, V. Rangnekar, A. Sinai, A.M. Rao, G.S. Rao, and K. Ambati for discussions. J.A. was supported by NEI/NIH grants R01EY018350, R01EY018836, R01EY020672, R01EY022238, R21EY019778, and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Senior Scientist Investigator Award (Research to Prevent Blindness, RPB); J.Z.B. by NIH K08EY021521, International Retinal Research Foundation, and American Health Assistance Foundation; M.E.K. by NIH K08EY021757; B.J.F., S.B., and M.E.K. by NIH T32HL091812 and UL1RR033173; G.N. by NIH R01AI063331 and R01AR052756; Y.H. by Alcon Japan Research award; W.W.H. by NIH P30EY021721; B.K.A. by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense; D.R.H. by NIH P30EY003040 and R01EY001545; J.F.K. and J.A.G. by NIH R01GM068414; J.W.Y. and D.-k.L. by Global Research Laboratory grant from MEST, Korea. Departmental unrestricted grants from RPB supported J.A. and W.W.H. University of Kentucky Physician Scientist Awards supported J.Z.B. and M.E.K. P.P. is a Senior Scholar from the Fonds de la Recherche en Santé du Québec (FRSQ). Several authors are named as inventors on patent applications filed by their universities relating to described technologies. V.T., Y.H., B.D.G., S.D., Y.K., W.G.C., J.Z.B., H.K., N.K., B.J.F., S.B., and M.E.K. performed experiments. W.W.H., V.A.C, S.L.P., J.F.K., J.A.G., M.P.M., J.W.Y., D.-k.L, D.R.H., P.P., and G.N. provided reagents. J.A. conceived and directed the project and wrote the paper with assistance from B.K.A., B.J.F., and B.D.G. All authors had the opportunity to discuss the results and comment on the manuscript.

PY - 2012/5/11

Y1 - 2012/5/11

N2 - Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.

AB - Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.

UR - http://www.scopus.com/inward/record.url?scp=84860883878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860883878&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2012.03.036

DO - 10.1016/j.cell.2012.03.036

M3 - Article

C2 - 22541070

AN - SCOPUS:84860883878

SN - 0092-8674

VL - 149

SP - 847

EP - 859

JO - Cell

JF - Cell

IS - 4

ER -

DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88

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