LRG1 as a novel therapeutic target in eye disease

Figures

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  Fig. 1. Structure of human Leucine-rich α-2 glycoprotein 1 (LRG1). A LRG1 is a 312 aa protein containing eight leucine-rich repeats (LRR), evolutionarily associated with protein–protein interaction, four N-linked and one O-linked glycosylation sites and two disulphide bonds. Following processing of the N-terminal signal peptide, the mature 50 kDa form of LRG1 is released into the extracellular space. B ALPHAFOLD2 prediction of LRG1 structure by deep learning algorithm [147]. β-sheet in green, helix in red.

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  Fig. 2. Pathological roles of LRG1. Increased levels of LRG1 are often reported in disease and several pathogenic mechanisms involving LRG1 have been proposed. LRG1 can play a part in the immune response by modulating lymphocyte number, granulopoiesis and neutrophil function and possibly by regulating TGFβ-mediated EC-leukocyte interactions. Many cell types like fibroblasts, epithelial cells, endothelial cells and pericytes can undergo trans-differentiation to myofibroblasts and contribute to fibrosis, and LRG1 has been implicated in the conversion of fibroblasts into fibrogenic myofibroblasts in a model of lung fibrosis. Leukostasis is a feature of DR in which neutrophils adhere to the non-perfused capillaries; LRG1 might be released by adherent neutrophils and mediate the EC damage which is associated with leukostasis. LRG1 upregulation during pathological angiogenesis is required for the TGFβ-induced angiogenic switch of ECs. Vascular instability/dysfunction follows altered physical and chemical interactions between ECs and pericytes; the TGFβ family of ligands and receptors plays an essential role in vessel maturation and homoeostasis by regulating these interactions, LRG1 has been…

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  Fig. 3. Context-dependent modulation of TGFβ pathway by LRG1. LRG1 can direct TGFβ signalling towards a specific pathway depending on the cell type and the context. During pathological angiogenesis/vascular dysfunction (left), LRG1 binds to Endoglin and switches the EC phenotype towards a pro-angiogenic state in an ALK1/SMAD-1,-5,-8-dependent fashion [23]. During fibrosis (right), LRG1 was shown to promote differentiation of fibroblasts into matrix-producing myofibroblasts by favouring the ALK5/SMAD-2,-3 pathway in an Endoglin-independent way [31]. Created with BioRender.com.

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  Fig. 4. LRG1 vasculopathic effects. A mature functional vessel is characterised by extensive pericyte coverage of the endothelium, and tight junctions between adjacent ECs to maintain barrier function. Confocal 3D reconstruction of murine retina showing high pericyte (yellow) coverage of ECs (magenta). In homoeostatic conditions, LRG1 is found at low levels in the circulation and is undetectable in the retinal tissue. In pathological scenarios, such as nvAMD and DR, LRG1 is upregulated both locally and systemically and contributes to vascular instability by altering pericyte-EC interactions and by directly promoting EC activation. These pathological alterations can result in loss of vessel homoeostatic function (i.e. barrier properties) and ultimately lead to the growth of new pathological vessels. Created with BioRender.com.