Aβ1–40 Oligomers Trigger Neutrophil Extracellular Trap Formation through TLR4- and NADPH Oxidase-Dependent Pathways in Age-Related Macular Degeneration

Abstract

Neutrophils participate in the advancement of the human innate immune system and respond to perceived endogenous and exogenous threats. As a response mechanism, neutrophil extracellular traps (NETs) form near pathogens and surrounding tissues during an immune response. Drusen is an important marker of Age-Related Macular Degeneration (AMD) and plays an important role in the course of AMD. Aβ1-40 is the main component of drusen. However, the relationship between NETs and AMD or Aβ1-40 is unclear. Here, we found elevated levels of NETs in the serum of AMD patients and elevated levels in the serum of mouse models. We also observed the accumulation of neutrophils in the mouse retina. In addition, the production of NETs was inhibited by PAD4 inhibitors, which can alleviate chronic inflammation. Moreover, we confirmed that Aβ1-40 can induce NETs formation via the Toll-like receptor 4 (TLR4) and neutrophil NADPH oxidase (NOX) pathways. Our study confirmed that the formation of NETs is induced by Aβ1–40, and the results suggest that NETs may play a vital role in AMD pathogenesis.

Macrophages Coordinate Immune Response to Laser-Induced Injury via Extracellular Traps

“…Recent research has uncovered evidence of ETs and their involvement in the pathophysiology of ocular diseases, including diabetic retinopathy, uveitis, and AMD (14, 15, 140). Relevant to our findings, Chen et al demonstrated that the amyloid β-protein Aβ1-40, the primary component of drusen, triggers the release of ETs through the activation of pro-inflammatory pathways (141). Their findings also demonstrated that PAD4 inhibitors effectively alleviate PL infiltration in the retina and, thus, chronic inflammation.…”

Macrophages coordinate immune response to laser-induced injury via extracellular traps

“…Recent research has uncovered evidence of ETs and their involvement in the pathophysiology of ocular diseases, including diabetic retinopathy, uveitis, and AMD [ 14 , 15 , 146 ]. Relevant to our findings, Chen et al demonstrated that the amyloid β-protein Aβ1-40, the primary component of drusen, triggers the release of ETs through the activation of pro-inflammatory pathways [ 147 ]. Their findings also demonstrated that PAD4 inhibitors effectively alleviate PL infiltration in the retina and, thus, chronic inflammation.…”

Innate immune biology in age-related macular degeneration

“…Neutrophil extracellular trap formation has previously been associated with retinal diseases (Ghosh et al, 2019;Wang et al, 2018). Aβ1-40 the main amyloidbeta component of the drusen characteristic of AMD may promote neutrophil extracellular trap formation in AMD through the Toll-like receptor 4 and neutrophil NADPH oxidase pathways (Chen et al, 2022). PAD4 inhibition in the mouse model led to reduced neutrophil extracellular trap formation, providing a potential therapeutic option for AMD (Chen et al, 2022).…”

“…Aβ1-40 the main amyloidbeta component of the drusen characteristic of AMD may promote neutrophil extracellular trap formation in AMD through the Toll-like receptor 4 and neutrophil NADPH oxidase pathways (Chen et al, 2022). PAD4 inhibition in the mouse model led to reduced neutrophil extracellular trap formation, providing a potential therapeutic option for AMD (Chen et al, 2022). PAD4 inhibition is currently used to treat rheumatoid arthritis and lupus, among other autoimmune diseases.…”

“…Targeting proteins such as PAD4 or C5a may produce similar results. Recent clinical trials for geographic atrophy have shown success at targeting the complement system (Coughlin et al, 2016;Chen et al, 2022). Therapeutic targets implicated in other neurodegenerative diseases such as glatiramer acetate, which is primarily used in MS has shown some efficacy in reversing AMD monocyte pathology in vitro (Gu et al, 2021).…”