Elastin turnover in ocular diseases: A special focus on age-related macular degeneration

Abstract

The extracellular matrix (ECM) and its turnover play a crucial role in the pathogenesis of several inflammatory diseases, including age-related macular degeneration (AMD). Elastin, a critical protein component of the ECM, not only provides structural and mechanical support to tissues, but also mediates several intracellular and extracellular molecular signaling pathways. Abnormal turnover of elastin has pathological implications. In the eye elastin is a major structural component of Bruch's membrane (BrM), a critical ECM structure separating the retinal pigment epithelium (RPE) from the choriocapillaris. Reduced integrity of macular BrM elastin, increased serum levels of elastin-derived peptides (EDPs), and elevated elastin antibodies have been reported in AMD. Existing reports suggest that elastases, the elastin-degrading enzymes secreted by RPE, infiltrating macrophages or neutrophils could be involved in BrM elastin degradation, thus contributing to AMD pathogenesis. EDPs derived from elastin degradation can increase inflammatory and angiogenic responses in tissues, and the elastin antibodies are shown to play roles in immune cell activity and complement activation. This review summarizes our current understanding on the elastases/elastin fragments-mediated mechanisms of AMD pathogenesis.

Keywords: Age-related macular degeneration; Complement activation; Elastase; Elastin; Elastin-derived peptides; Elastolytic enzymes; Extracellular matrix; Immune cell activity; Inflammation.

Fig. 1.. Elastic fiber formation and degradation.

Tropoelastin monomers are formed intracellularly, which then will be chaperoned and transported to the ECM by elastin binding proteins. At the cell surface elastin binding proteins will be released leading to tropoelastin self-aggregation or coacervation. Coacervation leads to next stages of elastic fiber assembly such as binding of fibulins, microfibrillar deposition, recruitment of lysyl oxidase, elastin cross-linking and mature fiber formation. Serine proteases such as neutrophil elastase & HTRA1, cysteine proteases like cathepsins K, V, L, S & B, and several metalloproteases (MMPs 2, 3, 7, 9, 12 & 14) are known to have elastolytic capability and can contribute to the degradation of insoluble elastic fibers to generate elastin fragments or EDPs. TIMPs and alpha-1 proteases such as alpha-1 antitrypsin are known elastase inhibitors that can prevent the degradation of elastic fibers. Abbreviations: TIMPs, Tissue inhibitors of metalloproteinases; MMPs, Matrix metalloproteinases; EDPs, Elastin-derived peptides.

Fig. 2.. Macular Bruch’s membrane elastin layer degradation in AMD.

Figure indicates schematic representation of eyeball, retina, and macula during health and AMD. Reduced macular elastin layer integrity and thickness have been reported in AMD patients compared to the age matched healthy subjects; BrM elastin layer thinning, calcification, and porosity were more evident and were corresponding to the distribution of CNV lesions in wet AMD macula.

Fig. 3.. Proposed mechanisms of elastin turnover in the pathogenesis of dry and wet AMD.

During AMD pathogenesis local inflammation or oxidative stress can upsurge the elastase secretion from RPE cells, infiltrating immune cells such as macrophages/neutrophils and microglia leading to elastin degradation and EDP generation. EDPs can bind to the GLB1 receptors present on the choroidal endothelial cells (Skeie et al., 2012). EDP binding to the endothelial cells can increase the MT1-MMP level (Robinet et al., 2005) and the phosphorylation of FAK/-PI3–K/Akt/mTOR (Gunda et al., 2013) pathway, leading to VEGF upregulation (Sounni et al., 2004), endothelial cell migration and pathological neovascularization. Collagen fragment α6(IV) NC1 can inhibit this elastin peptide mediated endothelial cell migration and angiogenesis (Gunda et al., 2013). Products of elastin degradation can also increase the autoantibody production and complement C3 overactivation (Annamalai et al., 2020), suggesting its possible role in RPE death and dry AMD pathogenesis. Abbreviations: RPE, Retinal Pigment Epithelium; MMP, matrix metalloproteinase; HTRA1, High-Temperature Requirement A Serine Peptidase 1; ELANE, Neutrophil Elastase/leukocyte elastase; EDP, Elastin Derived Peptides; GLB1, Galactosidase beta 1 receptor; MT1 MMP, Membrane Type 1 MMP; Collagen α6(IV) NC1, type IV collagen α-6 chain-derived non-collagenous domain; VEGF-A, Vascular Endothelial Growth Factor A; FAK/-PI3–K/Akt/mTOR, Focal adhesion kinase(FAK)/-phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)/mammalian target of rapamycin (mTOR).