Targeting inflammasomes and pyroptosis in retinal diseases-molecular mechanisms and future perspectives.

Retinal diseases encompass various conditions associated with sight-threatening immune responses and are leading causes of blindness worldwide. These diseases include age-related macular degeneration, diabetic retinopathy, glaucoma and uveitis. Emerging evidence underscores the vital role of the innate immune response in retinal diseases, beyond the previously emphasized T-cell-driven processes of the adaptive immune system. In particular, pyroptosis, a newly discovered programmed cell death process involving inflammasome formation, has been implicated in the loss of membrane integrity and the release of inflammatory cytokines. Several disease-relevant animal models have provided evidence that the formation of inflammasomes and the induction of pyroptosis in innate immune cells contribute to inflammation in various retinal diseases. In this review article, we summarize current knowledge about the innate immune system and pyroptosis in retinal diseases. We also provide insights into translational targeting approaches, including novel drugs countering pyroptosis, to improve the diagnosis and treatment of retinal diseases.

Regulatory T cell intravitreal delivery using hyaluronan methylcellulose hydrogel improves therapeutic efficacy in experimental autoimmune uveitis.

Autoimmune uveitis refers to several intraocular inflammation conditions, which are mediated by autoreactive T cells. Regulatory T cells (Tregs) are immunosuppressive cells that have shown potential for resolving various autoimmune diseases, including uveitis. However, poor donor cell dispersion distal to the injection site and plasticity of Treg cells in an inflammatory microenvironment can present obstacles for this immunotherapy. We assessed the use of a physical blend of hyaluronan and methylcellulose (HAMC) as immunoprotective and injectable hydrogel cell delivery system to improve the efficacy of Treg-based therapy in treating experimental autoimmune uveitis (EAU). We demonstrated that the Treg-HAMC blend increased both the survival and stability of Tregs under proinflammatory conditions. Furthermore, we found that the intravitreal HAMC delivery system resulted in a two-fold increase in the number of transferred Tregs in the inflamed eye of EAU mice. Treg-HAMC delivery effectively attenuated ocular inflammation and preserved the visual function of EAU mice. It significantly decreased the number of ocular infiltrates, including the uveitogenic IFN-γ+CD4+ and IL-17+CD4+ T cells. In contrast, intravitreal injection of Treg cells without HAMC only achieved marginal therapeutic effects in EAU. Our findings suggest that HAMC may become a promising delivery vehicle for human uveitis Treg therapy.

Multifunctional Interleukin-24 Resolves Neuroretina Autoimmunity via Diverse Mechanisms.

IL-24 is a multifunctional cytokine that regulates both immune cells and epithelial cells. Although its elevation is associated with a number of autoimmune diseases, its tolerogenic properties against autoreactive T cells have recently been revealed in an animal model of central nervous system (CNS) autoimmunity by inhibiting the pathogenic Th17 response. To explore the potential of IL-24 as a therapeutic agent in CNS autoimmunity, we induced experimental autoimmune uveitis (EAU) in wildtype mice and intravitreally injected IL-24 into the inflamed eye after disease onset. We found that the progression of ocular inflammation was significantly inhibited in the IL-24-treated eye when compared to the control eye. More importantly, IL-24 treatment suppressed cytokine production from ocular-infiltrating, pathogenic Th1 and Th17 cells. In vitro experiments confirmed that IL-24 suppressed both Th1 and Th17 differentiation by regulating their master transcription factors T-bet and RORγt, respectively. In addition, we found that intravitreal injection of IL-24 suppressed the production of proinflammatory cytokines and chemokines from the retinas of the EAU-inflamed eyes. This observation appears to be applicable in humans, as IL-24 similarly inhibits human retinal pigment epithelium cells ARPE-19. In conclusion, we report here that IL-24, as a multifunctional cytokine, is capable of resolving ocular inflammation in EAU mice by targeting both uveitogenic T cells and RPE cells. This study sheds new light on IL-24 as a potential therapeutic candidate for autoimmune uveitis.

Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunity.

BACKGROUND: Induction of autoantigen-specific Treg cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases. METHODS: In a model of experimental autoimmune uveitis (EAU) that mimics human uveitis, ocular inflammation was induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP). Mice were given intraperitoneal injection of αCD4 antibody (Ab) after the onset of disease, followed by administration of IRBP. EAU was evaluated clinically and functionally. Splenocytes, CD4+CD25- and CD4+CD25+ T cells were sorted and cultured with IRBP or αCD3 Ab. T cell proliferation and cytokine production were assessed. FINDINGS: The experimental approach resulted in remission of ocular inflammation and rescue of visual function in mice with established EAU. Mechanistically, the therapeutic effect was mediated by induction of antigen-specific Treg cells that inhibited IRBP-driven Th17 response in TGF-ß and IL-10 dependent fashion. Importantly, the Ab-mediated immune tolerance could be achieved in EAU mice by administration of retinal autoantigens, arrestin but not limited to IRBP only, in an antigen-nonspecific bystander manner. Further, these EAU-suppressed tolerized mice did not compromise their anti-tumor T immunity in melanoma model. INTERPRETATION: We successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis. FUNDING: This study was supported by the Natural Science Foundation of Guangdong Province and the Fundamental Research Fund of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center.