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

Abstract

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.

• Authors: Satomi Shiose, Yu Chen, Kiichiro Okano, Sanhita Roy, Hideo Kohno, Johnny Tang, Eric Pearlman, Tadao Maeda, Krzysztof Palczewski, Akiko Maeda
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 17 Pg. 15543-55 (Apr 29 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21383019 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ATP-Binding Cassette Transporters
• Abca4 protein, mouse
• TLR3 protein, mouse
• Toll-Like Receptor 3
• Alcohol Oxidoreductases
• Rdh8 protein, mouse
• Retinaldehyde

Topics

• ATP-Binding Cassette Transporters (genetics)
• Alcohol Oxidoreductases (deficiency, genetics)
• Animals
• Apoptosis
• Gene Expression Profiling
• Inflammation
• Mice
• Mice, Knockout
• Retinal Degeneration (etiology)
• Retinal Diseases (etiology)
• Retinaldehyde (physiology)
• Toll-Like Receptor 3 (physiology)