TLR2 bridges oxidative damage and complement-associated pathology and is a therapeutic target for age-related macular degeneration.

Abstract

Purpose : Age-related Macular Degeneration (AMD) is the primary cause of central vision loss in the developed world. Deposition of complement component 3 (C3) subjacent to retinal pigment epithelium (RPE) and increased oxidative protein modifications are pathological hallmarks of disease. Dysregulated activation of the alternative complement cascade is involved in AMD progression, however initiating factors driving C3 deposition remain elusive.

Methods : This study used multiple techniques including immunohistochemistry on human donor eye tissue, in vitro mechanistic assays and two mouse models of oxidative stress inducible retinal degeneration to determine the relationship between cellular and humoral components of the innate immune system and retinal degeneration.

Results : Here we show that oxidative-stress related protein modification 2-(w-carboxyethyl)pyrrole (CEP), a biomarker of AMD and a ligand for toll-like receptor 2 (TLR2) induces robust secretion of C3 and complement factor B (CFB), the initiating factor for alternative complement activation from the RPE. Moreover, C3 is secreted basolaterally from polarised RPE cells corresponding with C3d staining we observe in human AMD donor eyes. In the presence of normal human serum, CEP adducts promote complement proteolysis to completion resulting in sublytic membrane attack complex (MAC) formation and induction of MCP-1 chemokine, correlating with increased TLR2+ cells observed in the choriocapillaris of AMD donor eyes. MAC formation was inhibited using an anti-TLR2 neutralising antibody and a Mal peptide inhibitor. We show that C3 deposition, RPE atrophy and photoreceptor cell death are ameliorated by TLR2 blockade in oxidative stress models of retinal degeneration that mimic aspects of AMD and directly implicate TLR2 as a bridge between oxidative damage and complement-mediated pathology.

Conclusions : These findings indicate anti-TLR2 treatment has therapeutic utility for the pathology associated with dry AMD.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.