## 4 Discussion
IL-17A is mainly produced by Th17 cells and is a well-known factor mediating the inflammatory response in inflammatory and autoimmune diseases, and also in AMD [7]. In addition, IL-17A may co-stimulate the angiogenic effect of VEGF [7]. Furthermore, results of animal studies on laser-induced CNV have shown that IL-17A has the ability to stimulate neovascularization in choroid tissue by a mechanism independent of VEGF [7,25]. MCP-1/CCL2 is a protein molecule belonging to the CC chemokine family and can be produced by a variety of cell types, including fibroblasts, lymphocytes, macrophages and vascular endothelial cells [26]. MCP-1/CCL2 is an important factor in both acute inflammatory response by recruiting monocytes to the site of inflammation and chronic inflammatory response by regulating the penetrationof monocytes and macrophages into target tissues [27]. [PERSON] et al. revealed that IL-17A stimulation of human brain epithelial cells is associated with an increase in T\({}_{h}\)17 cell adherence, as well as an increase in MCP-1/CCL2 expression, leading to an increase in blood-brain barrier (BBB) permeability for inflammatory cells [28]. In this study, we observed a significant increase in serum IL-17A concentration in patients with nAMD after the initial loading phase of IVA, compared to the initial measurement. There were no significant differences between any of the MCP-1/CCL2 concentration measurements. The study conducted by [PERSON] et al. on vascular endothelial cell culture has shown that affibercept, after binding to VEGF-A, can promote an inflammatory response by the stimulation of TLR 4 with subsequent activation of the NF-kB signaling pathway [6], while other studies revealed a decrease in the concentration of MCP-1 and other proinflammatory and proangiogenic cytokines in aqueous humor after intravitreal administration of affibercept [11; 12]. To the best of our knowledge, our study is the first in which the effect of intravitreal anti-VEGF drugs on systemic levels of IL-17A and MCP-1/CCL2 was evaluated. The results of previous studies suggest that our findings, showing a significant increase in IL-17A concentration, secondary to repeated intravitreal injections of affibercept, may have several important therapeutic implications associated with anti-VEGF treatment. [PERSON] et al. showed that retinal cells, including retinal vascular endothelial cells, photoreceptors and Muller cells, have the ability to express both IL-17A receptor components--IL-17 RA and IL-17 RC. In addition, an increase in retinal vascular permeability was correlated with elevated IL-17A concentration. Interestingly, it was observed that IL-17A systemic ablation in mice was associated with significant changes in retinal tissue concentration of factors that are strongly involved in the development of retinal degenerative changes--reduction in MCP-1/CCL2, CCL5, CXCL1, CX3 CL1 and CXCL5, as well as an increase in TIMP-1 [29]. Furthermore, animal studies using Akita mice with induced diabetic retinopathy have shown that intravitreally injected IL-17A causes activation of the Act1 signaling pathway and subsequent IL-17A dose-dependent Muller cell dysfunction and promotion of retinal ganglion cell apoptosis, as well as both increased leukocyte adherence and retinal vascular permeability, which leads to enhanced BRB breakdown [30]. It was also proven that an increase in IL-17A leads to the stimulation of Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) signaling and, as a result, increased VEGF expression, which can accelerate CNV progression [31]. In vitro studies with tumor models have shown that IL-17A may be responsible for resistance to anti-VEGF antibody therapy in a VEGF-independent mechanism by stimulating the NF-kB and extracellular signal-regulated kinase (ERK) pathways, resulting in increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor involved in inflammation and tumorigenesis [32; 33] (Figure 3).