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Elevated Retina-Specific Expression of the Small Heat Shock Protein, A-crystallin, Is Associated with Photoreceptor Protection in Experimental Uveitis

¹From the Doheny Eye Institute and the ²Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California; the ³Division of Immunology, Beckman Research Institute, City of Hope, Duarte, California; the ⁴National Institutes of Health, Bethesda, Maryland; and the ⁵Jules Stein Eye Institute, University of California at Los Angeles, Los Angeles, California.

PURPOSE. During the early phase of experimental autoimmune uveitis (EAU), before macrophages infiltrate the retina and uvea, photoreceptor mitochondrial oxidative stress, nitration of photoreceptor mitochondrial proteins, and release of cytochrome c have been observed. However, no apoptosis has been detected during this phase. In this study, A-crystallin upregulation in the retina and its antiapoptotic protective role were evaluated in early EAU.

METHODS. Gene microarrays were first used to identify upregulated genes in retinas with early EAU. Among highly upregulated crystallins, A was confirmed by real-time polymerase chain reaction and Western blot, and the site of upregulation was localized by immunohistochemistry. The association of A-crystallin to nitrated cytochrome c and interaction with a procaspase-3 subunit was assayed. Photoreceptor apoptosis in A knockout mice was compared with that in wild-type animals with EAU, by using the terminal transferase dUTP nick-end labeling assay and polymerase chain reaction.

RESULTS. In early EAU, A-crystallin was increased 33-fold, and the site of increase was localized to the photoreceptor inner segments. This crystallin suppressed apoptosis by associating with the nitrated cytochrome c and p24. The association with nitrated cytochrome c, in particular, appeared to be restricted to nitrated cytochrome c, and thus, no association of non-nitrated cytochrome c was detected. The knockout mice showed signs of EAU development early and showed apoptosis in the retina; no such changes were seen in the wild-type control animals.

CONCLUSIONS. A-Crystallin is highly upregulated in the retina during early EAU. This upregulation is localized primarily in the photoreceptor inner segments, the site of mitochondrial oxidative stress. Further, in early EAU, the photoreceptors preferentially use A-crystallin to suppress mitochondrial oxidative stress-mediated apoptosis.

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