The cytokine IL-27 reduces inflammation and protects photoreceptors in a mouse model of retinal degeneration.

BACKGROUND: Retinal degenerative diseases are a group of conditions characterized by photoreceptor death and vision loss. Excessive inflammation and microglial activation contribute to the pathology of retinal degenerations and a major focus in the field is identifying more effective anti-inflammatory therapeutic strategies that promote photoreceptor survival. A major challenge to developing anti-inflammatory treatments is to selectively suppress detrimental inflammation while maintaining beneficial inflammatory responses. We recently demonstrated that endogenous levels of the IL-27 cytokine were upregulated in association with an experimental treatment that increased photoreceptor survival. IL-27 is a pleiotropic cytokine that regulates tissue reactions to infection, neuronal disease and tumors by inducing anti-apoptotic and anti-inflammatory genes and suppressing pro-inflammatory genes. IL-27 is neuroprotective in the brain, but its function during retinal degeneration has not been investigated. In this study, we investigated the effect of IL-27 in the rd10 mouse model of inherited photoreceptor degeneration. METHODS: Male and female rd10 mice were randomly divided into experimental (IL-27) and control (saline) groups and intravitreally injected at age post-natal day (P) 18. Retina function was analyzed by electroretinograms (ERGs), visual acuity by optomotor assay, photoreceptor death by TdT-mediated dUTP nick-end labeling (TUNEL) assay, microglia/macrophage were detected by immunodetection of IBA1 and inflammatory mediators by cytoplex and QPCR analysis. The distribution of IL-27 in the retina was determined by immunohistochemistry on retina cross-sections and primary Muller glia cultures. RESULTS: We demonstrate that recombinant IL-27 decreased photoreceptor death, increased retinal function and reduced inflammation in the rd10 mouse model of retinal degeneration. Furthermore, IL-27 injections led to lower levels of the pro-inflammatory proteins Ccl22, IL-18 and IL-12. IL-27 expression was localized to Muller glia and IL-27 receptors to microglia, which are key cell types that regulate photoreceptor survival. CONCLUSION: Our results identify for the first time anti-inflammatory and neuroprotective activities of IL-27 in a genetic model of retinal degeneration. These findings provide new insight into the therapeutic potential of anti-inflammatory cytokines as a treatment for degenerative diseases of the retina.

Exploring the role of interleukin-27 as a regulator of neuronal survival in central nervous system diseases.

Interleukin-27 is a pleiotropic cytokine that is involved in tissue responses to infection, cell stress, neuronal disease, and tumors. Recent studies in various tissues indicate that interleukin-27 has complex activating and inhibitory properties in innate and acquired immunity. The availability of recombinant interleukin-27 protein and mice with genetic deletions of interleukin-27, its receptors and signaling mediators have helped define the role of interleukin-27 in neurodegenerative diseases. Interleukin-27 has been well-characterized as an important regulator of T cell activation and differentiation that enhances or suppresses T cell responses in autoimmune conditions in the central nervous system. Evidence is also accumulating that interleukin-27 has neuroprotective activities in the retina and brain. Interleukin-27 is secreted from and binds to infiltrating microglia, macrophage, astrocytes, and even neurons and it promotes neuronal survival by regulating pro- and anti-inflammatory cytokines, neuroinflammatory pathways, oxidative stress, apoptosis, autophagy, and epigenetic modifications. However, interleukin-27 can have the opposite effect and induce inflammation and cell death in certain situations. In this review, we describe the current understanding of regulatory activities of interleukin-27 on cell survival and inflammation and discuss its mechanisms of action in the brain, spinal cord, and retina. We also review evidence for and against the therapeutic potential of interleukin-27 for dampening harmful neuroinflammatory responses in central nervous system diseases.

A Novel Use of Trypan Blue During Canalicular Glaucoma Surgery to Identify Aqueous Outflow to Episcleral and Intrascleral Veins.

PURPOSE: We describe a novel technique comprising the use of trypan blue to confirm aqueous outflow to collector channels and aqueous veins after goniotomy with the Kahook Dual Blade (New World Medical, Rancho Cucamonga, CA). Intraocular dyes have been safely used during ophthalmic surgery to evaluate the patency of the trabecular meshwork and collector channels. Further, trypan blue has been safely used to stain the anterior capsule of the lens in cataract surgery, to enhance visualization for capsulorhexis; similarly, trypan blue has been safely used to stain the trabecular meshwork for enhanced visualization during glaucoma angle surgery. Channelography enables evaluation of the collector channels during canaloplasty with fluorescein dye; episcleral fluid wave enables evaluation of the intraoperative structural patency of the conventional outflow system, from the anterior chamber to the episcleral and conjunctival distal collectors after Trabectome goniotomy (NeoMedix Corporation, Tustin, CA). PATIENTS AND METHODS: We evaluated 4 cases of glaucoma patients who underwent goniotomy with the Kahook Dual Blade to observe whether trypan blue could identify the patency of Schlemm's canal and aqueous egress to episcleral and intrascleral veins. RESULTS: We successfully confirmed the outflow pathway via Schlemm's canal and collector channels with trypan blue in 3 of the 4 cases. CONCLUSIONS: We conclude that trypan blue can be used safely to confirm both aqueous outflow and the patency of Schlemm's canal and aqueous veins during canalicular glaucoma surgery.