Microglia–Neutrophil Interactions Drive Dry AMD-like Pathology in a Mouse Model

Abstract

In dry age-related macular degeneration (AMD), inflammation plays a key role in disease pathogenesis. Innate immune cells such as microglia and neutrophils infiltrate the sub-retinal space (SRS) to induce chronic inflammation and AMD progression. But a major gap in our understanding is how these cells interact with each other in AMD. Here, we report a novel concept of how dynamic interactions between microglia and neutrophils contribute to AMD pathology. Using well-characterized genetically engineered mouse models as tools, we show that in the diseased state, retinal pigmented epithelial (RPE) cells trigger pro-inflammatory (M1) transition in microglia with diminished expression of the homeostatic marker, CX3CR1. Activated microglia localize to the SRS and regulate local neutrophil function, triggering their activation and thereby inducing early RPE changes. Ligand receptor (LR)-loop analysis and cell culture studies revealed that M1 microglia also induce the expression of neutrophil adhesion mediators (integrin β1/α4) through their interaction with CD14 on microglia. Furthermore, microglia-induced neutrophil activation and subsequent neutrophil-mediated RPE alterations were mitigated by inhibiting Akt2 in microglia. These results suggest that the Akt2 pathway in microglia drives M1 microglia-mediated neutrophil activation, thereby triggering early RPE degeneration and is a novel therapeutic target for early AMD, a stage without treatment options.

PGC‐1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age‐related macular degeneration

“…Such analysis would provide information about mechanism of the expression of the genes involved in senescence, antioxidant defence and autophagy, but it was not the aim of our study. Finally, changes in cellular phenotype and accumulation of inflammatory cells, such as microglia and neutrophils are possible in degenerative processes occurring in RPE during AMD development 4,27 . Therefore, it may be impossible to isolate RNAs specific to RPE by routine methods, including flash‐freezing.…”

“…We semi‐quantitatively determined the expression of proteins at different stages of autophagy flux. p62/SQSTM1 recognizes ubiquitinated perinuclear protein aggregates and the p62/SQSTM1‐tagged material is then isolated from the cytosol in p62/SQSTM1‐LC3 interaction‐guided autophagosome formation 27 . In the final step of the autophagy process, a lysosome is fused to the autophagosome resulting in the formation of the autolysosome followed by the degradation of its contents including ubiquitin, p62/SQSTM1 and LC3.…”

“…Finally, changes in cellular phenotype and accumulation of inflammatory cells, such as microglia and neutrophils are possible in degenerative processes occurring in RPE during AMD development. 4 , 27 Therefore, it may be impossible to isolate RNAs specific to RPE by routine methods, including flash‐freezing.…”

Crosstalk Between Microglia and Müller Glia in the Age-Related Macular Degeneration: Role and Therapeutic Value of Neuroinflammation

“…RPE displays several activities necessary for retinal homeostasis, including the transport of nutrients to photoreceptors and the removal of their metabolic wastes. In AMD pathology, RPE cells play a key role in modulating the activation and infiltration of innate immune cells including microglia, neutrophils, and monocytes [ 80 ]. Excessive oxidative stress altered protein assembling, dysfunction of mitochondrial form an internal feedback loop that leads to RPE failure, and allows the accumulation of misfolded proteins and abnormal lipids, resulting in the formation of drusen-like deposits.…”

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

“…Simultaneously, the blood-retinal barrier (BRB), which compartmentalizes blood and retinal parenchyma, alters its permeability characteristics, and the transcellular transport of PL increases (5). Thus, innate and adaptive immune cells are recruited from the circulation to the degenerating area, where they can interplay with microglia (6)(7)(8). An effective inflammatory response upon retinal damage requires the coordinated contribution of the local and infiltrated immune cells.…”