Toll-like receptor 3 is required for development of retinopathy caused by impaired all-trans-retinal clearance in mice

Chronic inflammation is an important component that contributes to many age-related neurodegenerative diseases, including macular degeneration. Here, we report a role for toll-like receptor 3 (TLR3) in cone-rod dystrophy (CORD) of mice lacking ATP-binding cassette transporter 4 (ABCA4) and retinol dehydrogenase 8 (RDH8), proteins critical for all-trans-retinal clearance in the retina. Increased expression of toll-like receptor-signaling elements and inflammatory changes were observed in Rdh8^-/- Abca4^-/- eyes by RNA expression analysis. Unlike 3-month-old Rdh8^-/- Abca4^-/- mice that developed CORD, 6-month-old Tlr3^-/- Rdh8^-/- Abca4^-/- mice did not evidence an abnormal retinal phenotype. Light-induced retinal degeneration in Tlr3^-/- Rdh8 ^-/- Abca4^-/- mice was milder than that in Rdh8 ^-/- Abca4^-/- mice, and a 2-fold increased TLR3 expression was detected in light-illuminated retinas of Rdh8^-/- Abca4 ^-/- mice compared with nonilluminated retinas. Poly(I-C), a TLR3 ligand, caused caspase-8-independent cellular apoptosis. Whereas poly(I-C) induced retinal cell death in Rdh8^-/- Abca4^-/- and WT mice both in vivo and ex vivo, this was not seen in mice lacking Tlr3. Far fewer invasive macrophage/microglial cells in the subretinal space and weaker activation of Muller glial cells were exhibited by Tlr3^-/- Rdh8 ^-/- Abca4^-/- mice compared with Rdh8^-/- Abca4^-/- mice at 3 and 6 months of age, indicating that loss of TLR3 inhibits local inflammation in the retina. Both poly(I-C) and endogenous products emanating from dying/dead retinal cells induced NF-κB and IRF3 activation. These findings demonstrate that endogenous products from degenerating retina stimulate TLR3 that causes cellular apoptosis and retinal inflammation and that loss of TLR3 protects mice from CORD.