Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy

Abstract

Inflammation is known to be involved in the progression of diabetic retinopathy. We have recently reported that vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα are higher than the respective serum levels in proliferative diabetic retinopathy (PDR) patients, and that vitreous levels of these cytokines are higher in PDR than in other non-inflammatory vitreoretinal diseases or uveitis associated with sarcoidosis. In the present study, we investigated inflammatory cytokines including Th17 cell-related cytokines in aqueous humor samples obtained from eyes with PDR, and analyzed the association between the aqueous humor and vitreous fluid levels of individual cytokines. The study group consisted of 31 consecutive type 2 diabetic patients with PDR who underwent cataract surgery and vitrectomy for vitreous hemorrhage and/or tractional retinal detachment. Undiluted aqueous humor was collected during cataract surgery, and then vitreous fluid was obtained using a 25G vitreous cutter inserted into the mid-vitreous cavity at the beginning of vitrectomy. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα levels in the aqueous humor and vitreous fluid were measured using a beads-array system. Although IL-17A was detected in the aqueous humor of eyes with PDR and the level correlated with IL-17A level in the vitreous fluid, both percent detectable and level of IL-17A in the aqueous humor were significantly lower than those in the vitreous fluid. Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFα levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFα level. The present study demonstrated that IL-17A level and detectable rate in the aqueous humor of patients with PDR are markedly lower than those in the vitreous fluid and aqueous IL-17A does not correlate with vitreous levels of other cytokines, and hence should not be used as a surrogate for IL-17A in the vitreous fluid.

A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis

“…Binding of SOCS1-KIR to the adaptor protein MAL dysregulates signaling from MyD88 and NF-kB. It is worth noting here that genetic deletion of either MyD88 or NF-kB leads to a resistance to autoimmune disorder (Mc Guire et al, 2013;van Loo et al, 2006).…”

“…Suppression of STAT1 and STAT3 leads to downregulation of the effects of the inflammatory cytokines IL-6 and IL-22 (a cytokine produced by Th17 cells), both of which are elevated in uveitis and related autoimmune disorders (Kim et al, 2016;Sainz-de-la-Maza et al, 2016). Uveitis patients were shown to have elevated levels of IL-22 (Takeuchi et al, 2017). Since IL-22 utilizes JAK2 and TYK2 for its signaling, the effect of this cytokine is likely to be dampened in the presence of R9-SOCS1-KIR.…”

“…Mice deleted in STAT3 in CD4 cells are resistant to EAU (Liu et al, 2008). Loss of NF-kB in CNS ameliorates autoimmune encephalomyelitis in mice (Mc Guire et al, 2013;van Loo et al, 2006). Suppression of IFN and IL-17A signaling, downregulation of chemokines that recruit inflammatory cells as well as preservation of barrier properties of RPE noted in ARPE-19 cells may have contributed to the protection seen in B10.RIII mice.…”

Interleukin-17: The Role for Pathological Angiogenesis in Ocular Neovascular Diseases

“…A subsequent study from the same research group further showed that the level of vitreous IL-17A was related significantly to IL-10, IL-22, and TNF-α levels in both vitreous and aqueous humor (Takeuchi et al 2017). One explanation is that the immune response of PDR involves both posterior and the anterior segments (Takeuchi et al 2017). Further investigation is needed to illustrate the IL-17 receptor distribution, the regulation of IL-17-related signaling pathway, and the relevant cytokines or mediators in the different segments of eyes in PDR.…”

“…It was found that the level of IL-17A (IL-17) level in the vitreous fluid was correlated significantly with the vitreous levels of cytokines including IL-4, IL-22, IL-31, and TNF-α. A subsequent study from the same research group further showed that the level of vitreous IL-17A was related significantly to IL-10, IL-22, and TNF-α levels in both vitreous and aqueous humor (Takeuchi et al 2017). One explanation is that the immune response of PDR involves both posterior and the anterior segments (Takeuchi et al 2017).…”