Interleukin-33 (IL-33) regulates mononuclear phagocytes in the degenerating retina

Abstract

Purpose : Neural retina loss in Age-related Macular Degeneration (AMD) is often associated with accumulation of mononuclear phagocytes (MP’s) in the photoreceptor layers. The factors that initiate recruitment of MP’s remain largely unknown. We hypothesize that IL-33 may regulate MP migration associated with atrophic AMD.

Methods : IL-33⁺ cells and infiltrating Iba1⁺ myeloid cells in retinas from AMD patients were examined by immunohistochemistry. IL-33 secretion was analyzed from rats exposed to bright light and from activated rat Muller cell line (rMC-1). Photoreceptor loss and myeloid cell infiltration in ST2^+/+ and ST2^-/- mice following constant light exposure (CLE) or RPE disruption by NaIO₃ treatment (20 mg/kg) was assessed by Spectral Domain Optical Coherence Tomography (SD-OCT), histology and flow cytometry. CCL-2 induction and myeloid cell infiltration were compared between ST2^+/+ and ST2^-/- mice following retina stress. The effect of monocyte depletion on photoreceptor survival was examined in ST2^+/+ and ST2^-/- mice. Efficacy of IL-33 blockade on photoreceptor survival following CLE was evaluated by subretinal injection of an Adeno-Associated Virus (AAV) expressing a soluble ST2.

Results : IL-33 is predominantly expressed in Muller cells of human macula and rodent retina. The number of IL-33⁺ Muller cells and Iba1⁺ myeloid cells was significantly increased in AMD lesion areas compared to non-lesion areas. IL-33 was released from activated Muller cells in vitro and in vivo upon retina injury. IL-33 released from Muller cells can function in an autocrine manner to induce CCL-2, a macrophage chemoattractant. Compared to ST2^+/+ mice, ST2^-/- mice showed reduced CCL-2 induction and accumulation of myeloid cells in the outer retina following retina stress. Deletion of ST2 or treatment with a soluble ST2 protein significantly protected photoreceptors from phototoxic injury. ST2 deficiency did not provide further protection of photoreceptors upon monocyte depletion indicating that infiltrating myeloid cells mediate IL-33/ST2-induced photoreceptor loss.

Conclusions : Our study demonstrates that IL-33 contributes to photoreceptor degeneration following retinal stress or injury by propagating MP recruitment to the outer retina and positions the IL-33/ST2 axis as a potential therapeutic target in atrophic AMD.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.