Investigating the effects of TLR2/MyD88 deficiency in mouse models of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness among older populations. Despite its global prevalence, a definitive cure for AMD remains elusive. To tackle this, we are focused on modulating the innate immune response. Toll-like receptor 2 (TLR2) responds to danger signals in the body and protects us from damaging pathogens. There are many endogenous danger signals in a degenerating retina that lead to aberrant TLR2 activation. This culminates in an over-activation of the innate immune response, leading to a dangerous cycle of chronic inflammation. Our primary aim was to use dry and wet AMD mouse models to study the effects of TLR2- and MyD88-dependent signalling on AMD progression. To elucidate the mechanisms underlying the protective effect of TLR2 inhibition, we employed a range of in-vitro assays to explore the role of MyD88 dependent signalling in leukocyte chemotaxis. We found TLR2 and MyD88 deficient mice were protected from RPE atrophy, immune cell infiltration and membrane attack complex (MAC) production in dry AMD mouse models. Analysis into the effect of TLR2 on wet AMD revealed differences in the staining pattern of remodelling collagen between WT and TLR2-/- mice, suggesting differences in the rates of wound resolution. We identified key transcription factors involved in TLR2-induced immune cell migration, and we hypothesise that this may be playing a role in the infiltration and accumulation of immune cells in the subretinal space which can contribute to AMD pathology. When pathogen- or damage-associated molecular patterns are recognised in the eye, the TLR mediated signalling will trigger a dynamic and robust inflammatory response. Our results highlight the critical role of TLR2 signalling in driving retinal inflammation and RPE degeneration. By targeting this pathway, we may unlock new avenues for the prevention and treatment of AMD.