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NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components

Nature Medicine volume 18, pages 791–798 (2012)Cite this article

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Abstract

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1β (IL-1β) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress–related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD–like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3−/− but not Il1r1−/− mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD.

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Figure 1: Drusen activates the NLRP3 inflammasome.
Figure 2: CEP (CEP-HSA), a component of drusen, can prime the NLRP3 inflammasome.
Figure 3: Complement factor C1Q, a component of drusen, activates the NLRP3 inflammasome.
Figure 4: Cleaved caspase-1 p10 colocalizes with activated macrophages in CEP-MSA–immunized mice.
Figure 5: NLRP3 is protective against laser-induced CNV lesion formation in an IL-1β–independent manner.
Figure 6: NLRP3 confers its protection against CNV lesion formation through its role in IL-18 production, which in turn regulates VEGF concentrations.

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Acknowledgements

The Ocular Genetics Unit at Trinity College Dublin is supported by the American Health Assistance Foundation (AHAF), Science Foundation Ireland (SFI), The Health Research Board of Ireland (HRB), Irish Research Council for Science Engineering and Technology (IRCSET), Enterprise Ireland (EI), Telemedicine and Advanced Technology Research Center (TATRC) and Fighting Blindness Ireland (FB-Ireland). S.L.D. and L.A.J.O. are supported by the SFI Immunology Research Centre (IRC) and the SFI Strategic Research Cluster (07/SRC/B1144). Support for the laboratory of J.G.H. was provided by the US National Institutes of Health through grant EY014240, the Macular Vision Research Foundation, Research to Prevent Blindness and the Llura and Gordon Gund Foundation. Support for the laboratory of R.G.S. was provided by the US National Institutes of Health through grants GM021249 and EY016813. Support for the laboratory of E.C.L. was from SFI grant number 08/RFP/MBT1363 and SFI Strategic Research Cluster 07/SRC/B1144. We would like to thank C. Woods, C. Murray, D. Flynn and R. Robertson for animal husbandry. The authors would also like to thank the Research Foundation at the Royal Victoria Eye and Ear Hospital for assistance in the acquisition of the Iridex laser system. We thank E. Latz (University of Bonn) for the provision of BMDMs expressing YFP-labeled ASC. We would like to acknowledge the expertise of K. Shadrach in isolating drusen from AMD donor eyes.

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Author notes

  1. Sarah L Doyle and Matthew Campbell: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland

    Sarah L Doyle, Andres Mori, Ed C Lavelle & Luke A J O'Neill

  2. Ocular Genetics Unit, Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland

    Matthew Campbell, Ema Ozaki, Paul F Kenna, Gwyneth Jane Farrar, Anna-Sophia Kiang, Marian M Humphries & Peter Humphries

  3. Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA

    Robert G Salomon

  4. The Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland.,

    Paul F Kenna

  5. Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA

    Joe G Hollyfield

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Contributions

S.L.D. and M.C. conceived of, designed and performed experiments and wrote the paper. E.O. performed experiments. R.G.S. prepared the CEP-HSA. A.M. genotyped all animals reported in the paper and isolated cells. P.F.K. performed ERG analyses. G.J.F., A.-S.K. and M.M.H. contributed to analysis of experiments and data. E.C.L. and L.A.J.O. conceived of experiments and analyzed data. J.G.H. isolated drusen and wrote the paper. P.H. conceived of and designed experiments and wrote the paper.

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Correspondence to Matthew Campbell.

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Doyle, S., Campbell, M., Ozaki, E. et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med 18, 791–798 (2012). https://doi.org/10.1038/nm.2717

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