Anti-IL8 monoclonal antibody

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide. Oxidative stress (OS), inflammation and genetics are considered the key pathogenic factors contributing to AMD development. Recent evidence shows the pro-inflammatory interleukin 17 (IL17) signaling is activated in AMD patients and promotes disease pathogenesis. However, the interplay between OS and IL17 signaling, and the regulatory mechanism of IL17 pathway are largely unknown. OS-induced retinal pigment epithelial cell (RPE) damage causes both the initial pathogenesis of AMD and secondary degeneration of rods and cones. Healthy RPE is essential for ocular immune privilege, however, damaged RPE cells can activate inflammatory response. In the present study, we identified IL17RA, the principle receptor of IL17 signaling, is one of the most upregulated inflammatory genes in human RPE cells upon OS exposure. The prominent increase of IL17RA was also observed in RPE and retina of an AMD-like mouse model. Knockdown of IL17RA in RPE cells prevented OS-induced RPE cell apoptosis and reduced the inflammatory response in both RPE and macrophages. Furthermore, we found that transcription factor KLF4 directly activates IL17RA expression, therefore, promotes the production of IL1 beta and IL8 in an IL17RA-dependent manner. In addition, the mRNA level of KLF4 isoform 2 was positively correlated with that of IL17RA in AMD patients. Together, our study demonstrates an unrevealed relationship between IL17RA and OS, and a new regulatory mechanism of IL17RA by KLF4 in RPE cells. These findings suggest that inhibition of IL17RA as a new potential therapeutic target for AMD through RPE protection and inflammatory suppression upon OS exposure.

Previous studies indicate that FGF21 has ability to repair nerve injury, but the specific mechanism is less studied. The present study was designed to investigate the effects of FGF21 on neurodegeneration changes in aging and diabetic mice and its mechanism. The diabetic and aging mice were used to study the effects of FGF21 on neurodegeneration and possible mechanisms. These mice were administrated with PBS, FGF21 or metformin once daily for 4 or 6 months, then the mechanism was studied in SH-SY5Y cells. The relevant gene expression for neurodegeneration was assessed by Quantitative Real Time-PCR, Western blot, H&E staining, immunohistochemistry and ELISA. The Western blot results of NeuN showed that FGF21 inhibited the loss of neurons in diabetic and aging mice. H&E staining results showed that the karyopyknosis and tissue edema around dentate gyrus and Cornu Amonis 3 (CA3) area of hippocampus were also inhibited by FGF21 in aging and diabetes mice. In vivo results revealed that administration of FGF21 suppressed the aggregation of tau and beta-amyloid(1-42) in the brains of diabetic and aging mice. The aggregation resulted in apoptosis of neurons. Meanwhile, FGF21 significantly reduced the expression of Iba1, NF-kappa B, IL6 and IL8 (p < 0.05) and enhanced anti-oxidant enzymes (p < 0.05) in aging and diabetic mice. In addition, the phosphorylation of AKT and AMPK alpha were increased by FGF21 treatment. In vitro experiment showed that the aggregation of tau and beta-amyloid(1-42) were-increased by LPS in SH-SY5Y cells, and FGF21 inhibited the aggregation through inhibiting the expression of NF-kappa B and promoting the phosphorylation of AKT and AMPK alpha. In conclusion, FGF21 attenuates neurodegeneration by reducing neuroinflammation and oxidant stress through regulating the NF-kappa B pathway and AMPK alpha/AKT pathway, which enhances the protective effect on mitochondria in neurons.