The NLR has been increasingly investigated as a systemic inflammation marker. Several studies have analyzed NLR in inflammatory conditions as an indicator of the disease, progression, and severity. For instance, positive NLR correlation was reported in diabetic retinopathy, worsening renal function in diabetic patients, end-stage renal disease, metabolic syndrome, ulcerative colitis, coronary artery disease, papillary microcarcinomas, pancreatitis, and cardiovascular diseases (Ulu et al., 2013; Azab et al., 2012; Turkmen et al., 2014; Buyukkaya et al., 2014; Okba et al., 2019; Torun et al., 2012; Papa et al., 2008; Seretis et al., 2013; Suppiah et al., 2013; Afari & Bhat, 2016; Cupp et al., 2020).
In AMD, Ilhan et al. (2015) has reported a significant difference in NLR values between dry and wet AMD (p=0.017), wet AMD and controls (p<0.001), and dry AMD and controls (p<0.001). Other reports have shown that elevated NLR was significantly correlated with wet AMD (Niazi et al., 2019). This study found that NLR values were slightly elevated in dry AMD patients compared to control; however, this was not statistically significant. The slight increase may correlate well with our newly diagnosed patient cohort.
Inflammatory mechanisms have been reported in the progressing of both dry and wet AMD (Xu et al., 2009). The accumulation of drusens between the retinal pigment epithelium and Bruch's membrane is a significant risk factor for the progression of AMD. These pathological drusens can trigger a cascade of chronic inflammatory and immune-mediated processes (Hageman et al., 2001; Rivera et al., 2017). Golestaneh et al. (2017) have shown that impairment in autophagic processes can contribute to drusens accumulation. In addition to the increased reactive oxygen species (ROS) and the reduced mitochondrial activity observed in retinal pigment epithelium cells cultured from human donors with AMD compared to healthy donors. With aging, mitochondria accumulate ROS damage and become dysfunctional, resulting in a notable decline in mitochondrial health, in addition to the decline of autophagic processes (Picca et al., 2017). The accumulation of oxidative damage is believed to be a leading cause of age-related degenerative diseases such as cancer, Alzheimer's disease, and AMD pathological processes (Chen & Xu, 2015; Datta et al., 2017; Golestaneh et al., 2017; Heppner et al., 2015; Matsui et al., 2000; Saijo et al., 2016).
Furthermore, the damaged mitochondria release components such as mitochondrial DNA (mtDNA), which induces inflammatory responses. A study by Lin et al., (2011) has shown that the increase in age-related mtDNA damage can lead to more macula lesions that positively correlate with AMD progression. Sensing mtDNA by cytosolic innate immune sensors, cyclic-GMP-AMP synthase, and the stimulator of interferon genes, lead to the production of Type I interferons (Type I IFNs) and other pro-inflammatory cytokines (Kumar, 2019). Additionally, mtDNA also triggers the assembly of a multiprotein complex known as the inflammasome (Shimada et al., 2012a). NOD-like receptors, and absent in melanoma 2-like receptors, are the two major sensors known to date responsible for the induction of inflammatory responses via the assembly of the inflammasome. Assembly of the inflammasomes leads to the production of inflammasome-mediated cytokines, IL-1β and IL-18, and eventually the pyroptotic type of cell death (Elinav et al., 2011; Keating et al., 2011). In relevance, mounting evidence suggested that mitochondria play an important role in activating the NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome. It has been demonstrated that mitochondrial damage and the cytosolic release of mitochondrial ROS and mtDNA increases NLRP3 activation (Shimada et al., 2012; Zhou R. et al., 2011). Therefore, inflammasome activation by mtDNA and the progression of AMD needs to be investigated. The role of the NLRP3 inflammasome in AMD pathogenesis has been shown using the amyloid-beta (Aβ) component of drusen as a stimulus which resulted in a robust inflammasome activation evident by elevated levels of IL-1β and IL-18. In addition to inflammasome-mediated-cytokines, stimulation with Aβ resulted in upregulation of the pro-inflammatory cytokines, IL-6 and TNF-α (Liu et al., 2013). Therefore, further studies are essential to investigate the levels of inflammatory markers including type I IFNs, IL-1β, IL-18, IL-6, and TNF-α in patients with dry and wet AMD compared to control participants.