Suppression of the Reactive Oxygen Response Alleviates Experimental Autoimmune Uveitis in Mice

Abstract

Reactive oxygen species (ROS) are produced by host phagocytes and play an important role in antimicrobial actions against various pathogens. Autoimmune uveitis causes blindness and severe visual impairment in humans at all ages worldwide. However, the role of ROS in autoimmune uveitis remains unclear. We used ROS-deficient (Ncf1−/−) mice to investigate the role of ROS in experimental autoimmune uveitis (EAU). Besides, we also used the antioxidant N-acetylcysteine (NAC) treatment to evaluate the effect of suppression of ROS on EAU in mice. The EAU disease scores of Ncf1−/− mice were significantly lower than those of wild-type mice. EAU induction increased the levels of cytokines (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-12, IL-17, and tumor necrosis factor (TNF)-α) and chemokines (monocyte chemoattractant protein (MCP)-1) in the retinas of wild-type mice but not in those of Ncf1−/− mice. EAU induction enhanced the level of NF-κB activity in wild-type mice. However, the level of NF-κB activity in Ncf1−/− mice with EAU induction was low. Treatment with the antioxidant NAC also decreased the severity of EAU in mice with reduced levels of oxidative stress, inflammatory mediators, and NF-κB activation in the retina. We successfully revealed a novel role of ROS in the pathogenesis of EAU and suggest a potential antioxidant role for the treatment of autoimmune uveitis in the future.

Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis

“…Reactive-oxygen species (ROS) are produced by enzymatic/nonenzymatic metabolic redox reactions, which can lead to various diseases and disorders, such as uveitis [ 21 ]. In particular, the redox protein thioredoxin (TRX) can produce free radicals, while TXNIP is an endogenous inhibitor of TRX.…”

“…TXNIP was a pivotal endogenous negative regulator of cellular redox balance [ 22 , 63 , 64 ] that was highly expressed in immune cells and played a role in regulating lymphocyte cycle progression and proliferation in the immune system [ 62 , 65 ]. Sheng-Min Hsu, et al have confirmed suppression of the ROS could alleviate EAU [ 21 ]. In addition, melatonin significantly attenuated ROS production in microglia to alleviate EAE [ 66 ].…”

Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…Since ROS activates NF-κB signaling, which modulates gene expression in diverse cellular processes such as innate immune response ( 29 , 30 ), we next determined if NF-κB plays were required for the expression of inflammatory transcription factors in our EAE model. To do this, we co-stained the active form of NF-κB (pNF-κB) with NeuN or CD11b ( Figure 6G ).…”

Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis

“…The expression of IL-4 is increased when EAU is induced by IRBP peptide 1-20 in CFA. Treating EAU mice with rapamycin or suppressing the reactive oxygen response both reduce the levels of IL-4 and other cytokines related to Th1 and Th17 cells, thus ameliorating EAU [ 59 , 159 ]. Data from a clinical study suggests that the levels of IL-4 increase in serum and AqH of patients with endogenous uveitis and BD, but the levels are relatively low in BD [ 160 ].…”