Abstract
Experimental autoimmune uveitis (EAU), a model of human uveitis, is an organ-specific, T cell-mediated autoimmune disease. Autoreactive T cells can penetrate the blood-retinal barrier, which is a physical defense composed of tight junction-linked retinal pigment epithelial (RPE) cells. RPE cells serve as antigen-presenting cells (APCs) in the eye since they express MHC class I and II and Toll-like receptors (TLRs). Although previous studies have shown that supplementation with TLR agonists exacerbates uveitis, little is known about how TLR signaling in the RPE contributes to the development of uveitis. In this study, we isolated the RPE from EAU mice, which were induced by active immunization (aEAU) or adoptive transfer of antigen-specific T cells (tEAU). The expression of TLRs on RPE was determined, and both aEAU and tEAU mice exhibited induced tlr7 expression. The TLR7 agonist R848 was shown to induce aggressive disease progression, along with significantly elevated levels of the uveopathogenic cytokine IL-17. Furthermore, not only IL-17 but also R848 appeared to enhance the inflammatory response and to impair the barrier function of the RPE, indicating that TLR7 signaling is involved in the pathogenesis of EAU by affecting the behaviors of the RPE and consequently allowing the infiltration of autoreactive T cells intraocularly. Finally, local application of shRNA against TLR7 delivered by recombinant AAV effectively inhibited disease severity and reduced IFN-γ and IL-17. Our findings highlight an immunomodulatory role of RPE TLR7 in EAU development and provide a potential therapeutic strategy for autoimmune uveitis.
Highlights
The blood-retinal barrier (BRB) is a physical barrier composed of a layer of tight junction-linked retinal pigment epithelial (RPE) cells that provides an impermeable shield to prevent cells and molecules from entering the tissue of the retina [1, 2]
We examined which Toll-like receptors (TLRs) were involved in the development of Experimental autoimmune uveitis (EAU), and the expression levels of different TLRs were analyzed in RPE cells from EAU mice
We revealed the significance of TLR7 signaling in the uveopathogenic inflammatory response and maintaining the barrier function of RPE cells
Summary
The blood-retinal barrier (BRB) is a physical barrier composed of a layer of tight junction-linked retinal pigment epithelial (RPE) cells that provides an impermeable shield to prevent cells and molecules from entering the tissue of the retina [1, 2]. The BRB separates the inner side of the eyes from the blood circulation and contributes to maintaining immune privilege in the ocular environment. Impairment of the BRB might cause the influx of immune cells; these cells might recognize rare selfantigens and trigger autoreactivity in the eye [4, 5]. Uveitis is one of the most common autoimmune diseases associated with ocular blindness and is responsible for 5-25% of legal blindness in the population [6]. Patients with autoimmune uveitis tend to have strong major histocompatibility complex (MHC) associations and exhibit ocular infiltration of autoreactive T cells in response to retinal antigens such as interphotoreceptor retinoid-binding protein (IRBP), retinal arrestin and recoverin [7]. Corticosteroids are still the major therapeutic agent used to treat uveitis [9], immunosuppressants (such as cyclosporin A, azathioprine and rapamycin) [10] and biologics (such as antiTNFa therapy) [11] are used as adjunctive therapies
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