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Eyeing Macular Degeneration — A Few Inflammatory Remarks
James T. Rosenbaum, M.D.
Age-related macular degeneration (AMD) is the
world’s leading cause of the loss of central vision. It is usually classed as one of two forms: a
dry form, characterized by the appearance of drusen (Fig. 1), which are proteinaceous collections
at the level of the retinal pigment epithelium,
and by atrophy of the retinal pigment epithelium;
and a wet form, in which neovascularization complicates the retinal changes. Like several other
chronic, progressive diseases associated with aging (e.g., Alzheimer’s disease and atherosclerosis),
inflammation contributes to the pathogenesis of
AMD. The role of inflammation is supported by
the detection of products of the immune system in
the drusen themselves1 and by the results of genomewide association studies, which have implicated several components of the complement cascade in the pathogenesis of this disease.2 Two
recent publications, one by Doyle et al.3 and the
other by Tarallo et al.,4 have shown that NLRP3,
a component of the innate immune system that
senses danger-associated molecular patterns, is implicated in macular degeneration. The two studies
are remarkably similar and remarkably different.
Mutations in NLRP3 have been identified as the
cause of uncommon autoinflammatory diseases
known as cryopyrin-associated periodic syndromes.5 NLRP3 joins with two other cytoplasmic proteins, ASC and procaspase-1, to form a
complex called the inflammasome. The inflammasome, in turn, activates the enzyme caspase 1,
which goes on to activate several intracellular
proteins, including interleukin-1β and interleukin-18. Insights gained from studies of the rare
cryopyrin-associated periodic diseases have thus
clarified the function of NLRP3 and have contributed to the appreciation that relatively common diseases such as gout and pseudogout are
also mediated by the inflammasome.
Doyle et al. found that drusen themselves activate NLRP3 (Fig. 2). Activation is also induced
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Figure 1. Ophthalmoscopic View of the Retina and Optic
Nerve in Age-Related Macular Degeneration (AMD).
The irregularly shaped yellow deposits (arrows) are
drusen. An arrowhead points to the optic nerve. Drusen
are characteristic of both wet and dry AMD. Choroidal
neovascularization, the hallmark of wet AMD, is absent
in this photo; accordingly, this represents dry AMD.
by the complement component C1Q or enhanced
by carboxyethylpyrrole, a protein modified by oxidative stress. Tarallo et al. also found that NLRP3
is activated in patients with AMD, but this group
used an RNA motif known as an Alu repeat to activate the inflammasome in mouse and tissueculture studies. They had previously reported
evidence supporting a role for Alu repeats in the
pathogenesis of AMD. Together, the two investigative teams have expanded the list of potential
triggers of caspase 1 — a list that already includes
such diverse chemicals as uric acid and aluminum
hydroxide.
In most instances in which the inflammasome
is activated, interleukin-1 becomes the major
n engl j med 367;8 nejm.org august 23, 2012
The New England Journal of Medicine
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clinical implications of basic research
Figure 2. The NLRP3 Inflammasome and Age-Related Macular Degeneration (AMD).
Two studies recently implicated NLRP3, a component of the inflammasome, in AMD. One of these studies3 suggested that NLRP3 expressed in myeloid cells inhibits choroidal neovascularization and thus protects against AMD. The other study4 suggested that the activation of NLRP3 in the retinal pigment epithelium leads to atrophy of this structure. Local factors that activate NLRP3 include drusen,
C1Q, Alu repeats, and carboxyethylpyrrole. Activated NLRP3 activates caspase-1, which activates interleukin-18, and this in turn could
disrupt choroidal neovascularization or destroy the retinal pigment epithelium.
“protagonist.” For example, the inherited diseases caused by mutations in NLRP3 were nearly
untreatable until recently, but they are now
known to respond dramatically to interleukin-1
blockade. Surprisingly, therefore, both groups concluded that the major consequence of activation
of the inflammasome in the retina is the production of interleukin-18. Doyle et al. believe that
the source of this cytokine is probably myeloid
cells. Although NLRP3 is usually expressed predominantly in bone marrow–derived cells, Tarallo
et al. contend that the retinal pigment epithelium
is primarily responsible for interleukin-18. (Interleukins, of which there are more than 36, are cytokines named for their role in communication
among leukocytes, but their expression is not confined to leukocytes.)
The two groups arrived at opposite conclusions
about the consequence of interleukin-18 in AMD.
Tarallo and colleagues found that interleukin-18
promotes damage to the retinal pigment epithelium in a mouse model that mimics aspects of the
dry form of AMD. Doyle and colleagues used a
mouse model of choroidal neovascularization, the
hallmark of wet AMD, and concluded that interleukin-18 inhibits new vessel formation; atrophy
of the retinal pigment epithelium is not prominent
in their model.
Thus, one group of authors concludes that
inflammation in AMD is harmful and the other
concludes that inflammation is beneficial. It is
possible that both groups are right and that interleukin-18 has a dual role in AMD. If so, interleukin-18 as a therapeutic agent will present a
Faustian dilemma, since delivering it might have
both a favorable action (i.e., blocking neovascu-
n engl j med 367;8 nejm.org august 23, 2012
The New England Journal of Medicine
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Copyright © 2012 Massachusetts Medical Society. All rights reserved.
769
clinical implications of basic research
larization) and an unfavorable action (i.e., destroying the retinal pigment epithelium) in the posterior portion of the eye. Inhibiting interleukin-18
might salvage the retinal pigment epithelium
while promoting new vessel growth. As the biology is clarified, new targets downstream from
interleukin-18 will likely emerge.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Departments of Ophthalmology, Medicine, and Cell
Biology, Oregon Health and Science University, Portland.
1. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen
associated with aging and age-related macular degeneration
contain proteins common to extracellular deposits associated
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with atherosclerosis, elastosis, amyloidosis, and dense deposit
disease. FASEB J 2000;14:835-46.
2. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C,
Farrer LA. Complement factor H polymorphism and age-related
macular degeneration. Science 2005;308:421-4.
3. Doyle SL, 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 2012;18:791-8.
4. Tarallo V, Hirano Y, Gelfand BD, et al. DICER1 loss and Alu
RNA induce age-related macular degeneration via the NLRP3
inflammasome and MyD88. Cell 2012;149:847-59.
5. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like
protein causes familial cold autoinflammatory syndrome and
Muckle-Wells syndrome. Nat Genet 2001;29:301-5.
DOI: 10.1056/NEJMcibr1204973
Copyright © 2012 Massachusetts Medical Society.
n engl j med 367;8 nejm.org august 23, 2012
The New England Journal of Medicine
Downloaded from nejm.org by Joyce Miller on August 28, 2012. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.