Toll-like Receptor 3 Is Required for Development of Retinopathy Caused by Impaired All-trans-retinal Clearance in Mice

作者：Shiose Satomi; Chen Yu; Okano Kiichiro; Roy Sanhita; Kohno Hideo; Tang Johnny; Pearlman Eric; Maeda Tadao; Palczewski Krzysztof^*; Maeda Akiko

来源：Journal of Biological Chemistry, 2011, 286(17): 15543-15555.

DOI：10.1074/jbc.M111.228551

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/microglialcells 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-kappa B 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.

• 出版日期2011-4-29