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IL-18 is not therapeutic for neovascular age-related macular degeneration

Nature Medicine volume 20, pages 1372–1375 (2014)Cite this article

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To the Editor:

Up to 50 million people worldwide are afflicted with the devastating blinding disease age-related macular degeneration (AMD)1,2,3. The vast majority of patients have the currently untreatable 'dry' or atrophic form of AMD, which is characterized by NLRP3 inflammasome–driven degeneration of the retinal pigment epithelium (RPE) supportive cell layer4,5. Blockade of the NLRP3 inflammasome is a next-generation therapeutic target in dry AMD; however, it was recently reported that inflammasome-mediated production of interleukin-18 (IL-18) potentially safeguards the retina against the other, often more visually devastating form of AMD—which patients with dry AMD are at greatly increased risk of developing—known as choroidal neovascularization (CNV)6. Therefore, before initiating inflammasome-targeting clinical trials, it is essential to directly and rigorously assess whether modulating IL-18 or the NLRP3 inflammasome affects RPE cell health and CNV.

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Figure 1: IL-18 intravitreous administration does not affect choroidal angiogenesis.
Figure 2: Glycerol, but not IL-18 deficiency, increases choroidal angiogenesis.

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Acknowledgements

We thank L. Toll, G.R. Pattison R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, K. Ambati and A. Uittenbogaard for technical assistance. J.A. was supported by National Eye Institute/US National Institutes of Health (NIH) grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672 and R01EY022238, the Doris Duke Distinguished Clinical Scientist Award, the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the Ellison Medical Foundation Senior Scholar in Aging Award, the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, a Foundation Fighting Blindness Individual Investigator Research Award, the Carl Reeves Foundation, a Harrington Discovery Institute Scholar-Innovator Award and a Research to Prevent Blindness departmental unrestricted grant. Y.H. was supported by an Alcon Japan Research award. T.Y. was supported by a Fight for Sight postdoctoral award. B.J.F. was supported by NIH T32HL091812 and UL1RR033173. A.B.-C. was supported by the Programme for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal) and a Bayer Global Ophthalmology Research Award. N.K. was supported by NIH K99EY024336 and the Beckman Initiative for Macular Research. B.D.G. was supported by the American Heart Association and the International Retinal Research Foundation. B.K.A. was supported by NIH R01EY017182 and R01EY017950, a Veterans Affairs Merit Award and the Department of Defense. G.N. was supported by NIH R01AI063331 and R01AR052756. D.R.H. was supported by NIH P30EY003040 and R01EY001545 and the Arnold and Mabel Beckman Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA

    Yoshio Hirano, Tetsuhiro Yasuma, Benjamin J Fowler, Valeria Tarallo, Reo Yasuma, Younghee Kim, Ana Bastos-Carvalho, Nagaraj Kerur, Bradley D Gelfand, Sasha Bogdanovich & Jayakrishna Ambati

  2. Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Takeshi Mizutani, Miho Nozaki & Yuichiro Ogura

  3. Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy

    Valeria Tarallo

  4. Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky, USA

    Bradley D Gelfand

  5. Department of Microbiology, Immunology and Human Genetics, University of Kentucky, Lexington, Kentucky, USA

    Bradley D Gelfand

  6. Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA

    Shikun He & David R Hinton

  7. Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA

    Shikun He & David R Hinton

  8. Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Xiaohui Zhang & Balamurali K Ambati

  9. Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Ryo Ijima, Hiroki Kaneko & Hiroko Terasaki

  10. Division of Dermatology, Kobe University School of Medicine, Chuo-ku, Kobe, Japan

    Hiroshi Nagai

  11. Department of Urology, Wakayama Medical University, Wakayama, Japan

    Isao Haro

  12. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Gabriel Núñez

  13. Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA

    Balamurali K Ambati

  14. Department of Physiology, University of Kentucky, Lexington, Kentucky, USA

    Jayakrishna Ambati

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Contributions

Y.H., T.Y., T.M., V.T., R.Y., Y.K., A.B.-C., N.K., B.D.G., S.B., S.H., X.Z., M.N., R.I. and H.K. performed experiments. G.N., I.H. and H.N. provided animals and reagents. J.A. and B.J.F. wrote the paper with assistance from A.B.-C. The project was jointly directed by J.A., D.R.H., B.K.A., M.N., H.K., Y.O. and H.T. All authors had the opportunity to discuss the results and comment on the manuscript.

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Correspondence to Jayakrishna Ambati.

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Competing interests

J.A. is named as an inventor on US and PCT patent applications filed by his employer, The University of Kentucky, pertaining to inflammasome-modulating strategies for AMD described in this manuscript. iVeena, Inc., co-founded by B.K.A. and J.A., has licensed technologies related to AMD from The University of Kentucky.

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Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 6774 kb)

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Hirano, Y., Yasuma, T., Mizutani, T. et al. IL-18 is not therapeutic for neovascular age-related macular degeneration. Nat Med 20, 1372–1375 (2014). https://doi.org/10.1038/nm.3671

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